Pharmacology Books

Book SynopsisThis title primarily focuses on the functional mechanisms and roles of Ca2+ channels in the central nervous system, and the effects of Ca antagonists on cytosolic CA2+ by blocking voltage sensitive channels. These findings are an important contribution to understanding the mechanisms of brain dysfunctions, including Alzheimer's disease, cerebral ischemia and affective disorders, as well as the effects of cytosolic CA2+ modulators on neuronal cell death. In addition the results of clinical trials are reported using typical and atypical Ca antagonists in the treatment of neuropsychiatric diseases.An essential reference to some of the most current and vital research into Ca antagonists as therapeutic agents, this monograph is invaluable for all clinical and pre-clinical researchers active in the multidisciplinary fields of neuroscience, including: psychopharmacology, molecular biology, behavioral pharmacology, neuropharmacology, and electrophysiology and immunology. Investigators of Ca2+ dynamics and brain dysfunction especially will find this book useful in the development of novel drugs to treat neuropsychiatric diseases.

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Book SynopsisDrug resistance is a growing problem in today's society. Successful drugs are constantly being developed but there is always the risk that a small percent of the drug's target will be immune. These survivors can then lead to a new population, resistant to the action of this drug. New drugs are continuously under development to combat this problem, but these can, in turn, lead to new resistant populations. This problem is universal whether the target is to destroy a deadly virus, or an insect which is ravaging crop production. Development of new drugs is difficult and time consuming so it is of crucial importance that we understand the processes behind drug resistance. "Molecular Genetics of Drug Resistance" forms a vital and timely review of the genetic processes behind drug resistance. Starting with an overview of the area, each chapter focuses on a particular target with important sections on drug resistance in malaria and in cancer. Each chapter has been written by an acknowledged expert in the field and the careful work of the editors has ensured a consistent approach and presentation. Table of ContentsNatural selection and drug resistance; drug and pesticide resistance in fungi; viral drug resistance; herbicide resistance; drug resistance in insects; the mechanisms of drug action and resistance in malaria; multidrug resistance in mammalian cells mediated by members of the ATP-binding cassette superfamily; drug resistance in cancer chemotherapy; oxidative stress responses in mammalian cells; modulation and circumvention of drug resistance.

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Book SynopsisIt is anticipated that submicron emulsion and lipid suspension will find numerous and novel medical applications in the near future. The purpose of this multi-authore book is to provide the reader with an up-to-date general overview of submicron emulsions and lipid suspensions (solid lipid nanoparticles) as well as to emphasize the various methods of preparation, characerization, evaluation and potential applications in various therapeutic areas.Leading authors have contributed to this unique book which contains all state of the art and detailed knowledge related to the physico-chemical, pharmaceutical and medical aspects of these most interesting but complex dosage forms, thus making this information easily available to the reader. This book will be of interest to scientists working in the field of drug delivery and targeting in universities as well as in the pharmaceutical, food, cosmetic, veterinary and chemical industries.Table of Contents1. Introduction and Overview Part 1. Intravenous Fat Emulsions 2. Perspectives on the Use of Intravenous Lipid Emulsions in Man 3. Particle-Sizing Technologies for Submicron Emulsions 4. Biofate of Fat Emulsions Part 2. Submicron Emulsions as Therapeutic Delivery Systems 5. Design and Evaluation of Submicron Emulsions as Colloidal Drug Carriers for Intravenous Administration 6. Submicron Emulsions as Drug Carriers for Tropical Administration 7. Emulsions of Supercooled Melts - A Novel Drug Delivery System 8. Submicron Lipid Suspensions (Solid Lipid Nanoparticles) Versus Lipid Nanoemulsions: Similarities and Differences 9. Solid Lipid Nanoparticles (SLN) for Controlled Drug Delivery Part 3. Perfluorochemical Submicron Emulsions 10. The Design and Engineering of Oxygen-Delivering Fluorocarbon Emulsions

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Book SynopsisThis book focuses on applications of compound library design and virtual screening to expand the bioactive chemical space, to target hopping of chemotypes to identify synergies within related drug discovery projects or to repurpose known drugs, to propose mechanism of action of compounds, or to identify off-target effects by cross-reactivity analysis. Both ligand-based and structure-based in silico approaches, as reviewed in this book, play important roles for all these applications. Computational chemogenomics is expected to increase the quality and productivity of drug discovery and lead to the discovery of new medicines.Table of ContentsForeword. Chemogenomics Approaches for the Quantitative Comparison of Biological Targets. Considerations on the Drug-like Chemical Space. Chemogenomic Protein-Family Methods in Drug Discovery: Profile-QSAR and Kinase-Kernel. Virtual Screening and Target Fishing for Natural Products Using 3D Pharmacophores. Computational Analysis of Ligand Binding Pockets. Binding Site Similarity Search to Identify Novel Target-Ligand Complexes. ChemProt: A Disease Chemical Biology Database. Scientific Requirements for the Next Generation Semantic Web-based Chemogenomics and Systems Chemical Biology Molecular Information System OPS. Index.

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Book SynopsisHydrogels are an emerging area of interest in medicine as well as pharmaceutics, and their physico-chemical characterization is fundamental to their practical applications. Compared with synthetic polymers, polysaccharides that are widely present in living organisms and come from renewable sources are extremely advantageous for hydrogel formation. Furthermore, polysaccharides are usually non-toxic and biocompatible and show a number of peculiar physico-chemical properties that make them suitable for a wide variety of biomedical applications. This book bridges the gap between the preparation of hydrogels and their characterization techniques. It aims to offer a valid support that can help the readers find appropriate keys to open the doors to the complex world of polysaccharide hydrogels.Trade Review"This book unveils the secrets of polysaccharide hydrogels that make them invaluable tools in the biomedical field. It presents elegant approaches to preparing hydrogels, techniques for a very detailed characterization of polysaccharides and their hydrogels, and recent applications."— Prof. Carmen Alvarez-Lorenzo, University of Santiago de Compostela, Spain"This book is one of the first to cover all the aspects of polysaccharide hydrogels from the basic aspects of chemistry and characterization to their biological relevance and medical applications and is a great and comprehensive answer to the first questions concerning hydrogels."— Prof. Pierre Weiss, University of Nantes, France"‘The gel is easier to recognize than to define (Dorothy Jordan Lloyd, 1926). This book gives significant answers to this ‘old’ but still intriguing statement as it brings together most of the up-to-date information on the hot topic of hydrogels obtained from polysaccharides, and their preparation, characterization and application in the field of pharmaceutics."— Prof. Gaetano Giammona, University of Palermo and The Biophysics Institute, ItalyTable of ContentsIntroduction. Hydrogels. Rheological Characterization of Hydrogels. Hydrogel Mesh Size Evaluation. Dynamic Light Scattering. NMR Methodologies in the Study of Polysaccharides. Small-Angle Neutron Scattering of Polysaccharide Hydrogels. The Method of Small-Angle X-ray Scattering and Its Application to the Structural Analysis of Oligo- and Polysaccharides in Solution. Stimuli Responsive Polysaccharide-Based Hydrogels. Properties and Biomedical Applications of Gellan Gum Hydrogels. Polysaccharide Hydrogels with Magnetic Nanoparticles. Physical and Chemical Hyaluronic Acid hydrogels and Their Biomedical Applications. Alginate Hydrogels: Properties and Applications. Polysaccharide Hydrogels: The Present and the Future.

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Book SynopsisChapter 1. Tropane Alkaloids: A Biologically Important Group of Nitrogen Containing Heterocyclic Phyto-Secondary Metabolites.- Chapter 2. Plant Sources of Tropane Alkaloids.- Chapter 3. Chemistry of Tropane Alkaloids: A Comprehensive Study of Biologically Important Group of Nitrogen Containing Heterocyclic Phyto-Secondary Metabolites.- Chapter 4. Biosynthesis of Tropane Alkaloids.- Chapter 5. Pharmacology of Tropane alkaloids.- Chapter 6. Tropane alkaloids in food commodities - occurrence in food and feed.- Chapter 7. Edible plant sources containing low and non-toxic levels of tropane and nortropane alkaloids.- Chapter 8. Tropane Alkaloids: Biosimilar and Biopharmaceutics.- Chapter 9. Tropane Alkaloids in vitro production, Current status, and Perspectives.- Chpter 10. Production of Important Pharmaceutical Compound, Tropane Alkaloids through Metabolic Engineering.- Chapter 11. Cultivation of Tropane Alkaloid yielding plants.- Chapter 12. Micropropagation of Tropane Alkaloid Yielding plants.- Chapter 13. Cocaine – a stimulant tropane alkaloid drug and its regulation.

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Book SynopsisTrade ReviewThe dearth of promising new treatments for many a serious disease remains a major challenge not just for the pharmaceutical industry but for all of society. In this exhaustively researched book, Brent R. Stockwell surveys the history of drug development and offers insightful suggestions for innovative new approaches. This is critical reading for the many involved in and concerned about this urgent issue. -- Robert Bazell, chief science correspondent, NBC News, and author of Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer This is a terrific book! Stockwell's writing is clear and engaging as he presents a thoughtful analysis of drug development that can be understood and appreciated by a diverse readership. Stockwell beautifully combines scientific history and personal anecdotes with clear explanations of the principles and practices of chemical biology to make a fascinating story of the past, present, and future of drug discovery. His book is informative, accurate, and a good read all put together. -- Geoffrey Cooper, Boston University, author of The Cell: A Molecular Approach and Oncogenes This is a truly wonderful book. Stockwell's writing will open the door to a universe that many readers may know little about. Drugs are born, biotech companies are created, scientists' careers are made and unmade, egos are raised and dashed. This book is so readable, it is an absolute page-turner. Yet it is also authoritative and scientifically sophisticated, managing to distill a complex, changing field into a beautifully written, well-crafted story. -- Siddhartha Mukherjee, Columbia University, author of The Emperor of All Maladies: A Biography of Cancer By providing accessible explanations for the underlying biological and chemical principles that apply to the complex solutions he describes, Stockwell enables even the scientifically unsophisticated reader to gain a wider perspective on what future disease treatment might entail. Publishers Weekly This very readable, even exciting work takes us through the medical breakthroughs of the past century. Globe and Mail This book deserves a readership, and there is certainly a need for it. As a drug companyresearcher, I have often wished that more people understood what the field was likeand how simultaneously fascinating and frustrating it can be. -- Derek B. Lowe Cell In this well-researched look into the complexities of making medicines, a chemical biologist gives a history of drug making and details innovative methods of drug discovery. Science News Despite our current political paralysis, government leaders should listen to Stockwell and be certain to advance our capacity to generate the drugs that our society and the world need. Harvard Magazine The book is well organized and includes many interesting, clever analogies to explain what can be complicated scientific problems. Choice An engaging and rewarding read... -- Donald C. Lo Journal of Clinical Investigation The reader is not only left with a satisfying overview of the proud history and future challenges of finding new medicines but also encouragement that Stockwell and his contemporaries are creatively committed to academic drug discovery. -- David Kroll Nature Chemistry Stockwell writes well-his prose is accessible to the educated reader, irrespective of his or her background. All of the personalities, errors and successes in contemporary drug discovery are presented. Stockwell enlivens their stories with anecdotes... -- Garrett A. FitzGerald Nature Medicine It is impossible to read this relatively short book...without being captured by the author's optimism about the future of drug development. -- Robert C. Young, M.D. Oncology TimesTable of ContentsList of Illustrations Preface Acknowledgments Abbreviations Part I. The Vanishing Cures 1. The Drug Discovery Crisis 2. A New Science of Molecules 3. The Birth of the First Cancer Drugs 4. A New Company Creating Drug Combinations 5. The Undruggable RAS Protein 6. The Druggable Genome Part II. The Path to the Next Generation of Medicines 7. Peering Inside Proteins 8. The Nature of Interactions Between Proteins 9. From Protein-Protein Interactions to Personalized Medicines 10. A Revolution in Peptide Synthesis 11. A Vast Array of Drug Candidates 12. Moving Outside the Small Molecule Box 13. Accelerating the Arrival of Next-Generation Drugs Notes Glossary Index

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Book SynopsisThis is practical clinincal guide for dispensing physicians and mental health professionals who need to know the important risks and medication reactions unique to the female physiology. Readers will find information on all the key drug classes and prescription guidelines for the treatment of psychiatric disorders.

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Book SynopsisSevere Dementia is a clinical text giving clear guidance on the management of all forms of severe dementia. It covers diagnosis, reviews all therapeutic interventions and includes chapters on the ethical, legal and social aspects of care of these patients.Trade Review"This is an excellent book for those interested in the care of patients with sever dementia." (Doody's Health Services)Table of ContentsList of contributors. Introduction. PART 1: INTRODUCTORY. Chapter 1: Assessment and Diagnosis of Severe Dementia (Paul Newhouse and Joseph Lasek). Chapter 2: Neurochemistry of Severe Dementia (Sally I. Sharp, Paul T. Francis and Clive G. Ballard). Chapter 3: The Molecular Pathology of Severe Dementia (Clive Holmes). PART 2: CLINICAL FEATURES OF SEVERE DEMENTIA. Chapter 4: Cognitive Functions in Severe Dementia (Judith Saxton and François Boller). Chapter 5: Behavioural and Psychological Symptons of Dementia – Agitation (E. Jane Byrne and Deborah Collins). Chapter 6: Depression in Severe Dementia (Kate Bielinski and Brian Lawlor). Chapter 7: Physical Aspects of Severe Alzheimer’s Disease (Bruno Vellas). Chapter 8: Clinical Features of Severe Dementia: Staging (Barry Reisberg, Jerzy Wegiel, Emile Franssen, Sridhar Kadiyala, Stefanie Auer, Liduïn Souren, Marwan Sabbagh and James Golomb). Chapter 9: Clinical Features of Severe Dementia: Function (Serge Gauthier). PART 3: MANAGEMENT. Chapter 10: Drug Treatment: Memantine (Anton P. Porsteinsson and Pierre N. Tariot). Chapter 11: Drug Treatment: Cholinesterase Inhibitors (Michael Woodward and Howard Feldman). Chapter 12: Drug Treatment: Treatment of Behavioural and Psychological Symptoms of Dementia with Neuroleptics (Peter Paul De Deyn). Chapter 13: Non-pharmacological Treatment of Severe Dementia: An Overview (Ross Overshott and Alistair Burns). Chapter 14: Non-pharmacological Treatment of Severe Dementia: the Seattle Protocols (Rebecca G. Logsdon, Linda Teri and Sue M. McCurry). Chapter 15: Care by Families for Late Stage Dementia (Steven H. Zarit and Joseph E. Gaugler). Chapter 16: Person-centred Care for People with Severe Dementia (Murna Downs, Neil Small and Katherine Froggatt). Chapter 17: Palliative Care in Patients with Severe Dementia (Raymond Koopmans, H. Roeline W. Pasman and Jenny T. van der Steen). Chapter 18: Narrative Ethics and Ethical Narratives in Dementia (Clive Baldwin). Chapter 19: Health Economics of Severe Dementia (Anders Wimo and Bengt Winblad). Index.

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Book SynopsisWritten in an accessible style, Medicinal Chemistry: An Introduction, Second Edition carefully explains fundamental principles of the subject while assuming little in the way of prior knowledge. The book focuses on the chemical principles used for drug discovery and design covering physiology and biology where relevant.Trade Review"The many strengths of this introductory text include its seamless integration of biochemistry and pharmacology to direct drug discovery." (Journal of Medicinal Chemistry, September 2008)Table of ContentsPreface to the First Edition xv Preface to the Second Edition xvii Acknowledgements xix Abbreviations xxi 1 An introduction to drugs, their action and discovery 1 1.1 Introduction 1 1.2 What are drugs and why do we need new ones? 1 1.3 Drug discovery and design: a historical outline 3 1.3.1 The general stages in modern-day drug discovery and design 7 1.4 Leads and analogues: some desirable properties 9 1.4.1 Bioavailability 9 1.4.2 Solubility 10 1.4.3 Structure 10 1.4.4 Stability 11 1.5 Sources of leads and drugs 14 1.5.1 Ethnopharmaceutical sources 15 1.5.2 Plant sources 15 1.5.3 Marine sources 17 1.5.4 Microorganisms 18 1.5.5 Animal sources 20 1.5.6 Compound collections, data bases and synthesis 20 1.5.7 The pathology of the diseased state 21 1.5.8 Market forces and ‘me-too drugs’ 21 1.6 Methods and routes of administration: the pharmaceutical phase 21 1.7 Introduction to drug action 24 1.7.1 The pharmacokinetic phase (ADME) 25 1.7.2 The pharmacodynamic phase 32 1.8 Classification of drugs 33 1.8.1 Chemical structure 33 1.8.2 Pharmacological action 34 1.8.3 Physiological classification 34 1.8.4 Prodrugs 35 1.9 Questions 35 2 Drug structure and solubility 37 2.1 Introduction 37 2.2 Structure37 2.3 Stereochemistry and drug design 38 2.3.1 Structurally rigid groups 38 2.3.2 Conformation 39 2.3.3 Configuration 41 2.4 Solubility 44 2.4.1 Solubility and the physical nature of the solute 44 2.5 Solutions 46 2.6 The importance of water solubility 47 2.7 Solubility and the structure of the solute 49 2.8 Salt formation 50 2.9 The incorporation of water solubilising groups in a structure 52 2.9.1 The type of group 52 2.9.2 Reversible and irreversible groups 53 2.9.3 The position of the water solubilising group 53 2.9.4 Methods of introduction 54 2.9.5 Improving lipid solubility 59 2.10 Formulation methods of improving water solubility 59 2.10.1 Cosolvents 59 2.10.2 Colloidal solutions 59 2.10.3 Emulsions 60 2.11 The effect of pH on the solubility of acidic and basic drugs 61 2.12 Partition 63 2.12.1 Practical determination of partition coefficients 65 2.12.2 Theoretical determination of partition coefficients 66 2.13 Surfactants and amphiphiles 66 2.13.1 Drug solubilisation 69 2.13.2 Mixed micelles as drug delivery systems 71 2.13.3 Vesicles and liposomes 72 2.14 Questions 72 3 Structure–activity and quantitative structure relationships 75 3.1 Introduction 75 3.2 Structure–activity relationship (SAR) 76 3.3 Changing size and shape 77 3.3.1 Changing the number of methylene groups in chains and rings 77 3.3.2 Changing the degree of unsaturation 78 3.3.3 Introduction or removal of a ring system 78 3.4 Introduction of new substituents 80 3.4.1 Methyl groups 81 3.4.2 Halogen groups 83 3.4.3 Hydroxy groups 84 3.4.4 Basic groups 84 3.4.5 Carboxylic and sulphonic acid groups 85 3.4.6 Thiols, sulphides and other sulphur groups 85 3.5 Changing the existing substituents of a lead 86 3.6 Case study: a SAR investigation to discover potent geminal bisphosphonates 87 3.7 Quantitative structure–activity relationship (QSAR) 90 3.7.1 Regression analysis 93 3.7.2 The lipophilic parameters 94 3.7.3 Electronic parameters 99 3.7.4 Steric parameters 102 3.8 Questions 110 4 Computer-aided drug design 113 4.1 Introduction 113 4.1.1 Models 114 4.1.2 Molecular modelling methods 115 4.1.3 Computer graphics 116 4.2 Molecular mechanics 117 4.2.1 Creating a molecular model using molecular mechanics 120 4.3 Molecular dynamics 123 4.3.1 Conformational analysis 124 4.4 Quantum mechanics 124 4.5 Docking 127 4.5.1 De novo design 128 4.6 Comparing three-dimensional structures by the use of overlays 130 4.6.1 An example of the use of overlays 132 4.7 Pharmacophores and some of their uses 133 4.7.1 High-resolution X-ray crystallography or NMR 133 4.7.2 Analysis of the structures of different ligands 134 4.8 Modelling protein structures 135 4.9 Three-dimensional QSAR 136 4.9.1 Advantages and disadvantages 140 4.10 Other uses of computers in drug discovery 141 4.11 Questions 143 5 Combinatorial chemistry 145 5.1 Introduction 145 5.1.1 The design of combinatorial syntheses 147 5.1.2 The general techniques used in combinatorial synthesis 148 5.2 The solid support method 148 5.2.1 General methods in solid support combinatorial chemistry 150 5.2.2 Parallel synthesis 152 5.2.3 Furka’s mix and split technique 155 5.3 Encoding methods 157 5.3.1 Sequential chemical tagging 157 5.3.2 Still’s binary code tag system 160 5.3.3 Computerised tagging 161 5.4 Combinatorial synthesis in solution 161 5.4.1 Parallel synthesis in solution 162 5.4.2 The formation of libraries of mixtures 163 5.4.3 Libraries formed using monomethyl polyethylene glycol (OMe-PEG) 164 5.4.4 Libraries produced using dendrimers as soluble supports 164 5.4.5 Libraries formed using fluorocarbon reagents 165 5.4.6 Libraries produced using resin-bound scavenging agents 166 5.4.7 Libraries produced using resin-bound reagents 168 5.4.8 Resin capture of products 168 5.5 Deconvolution 169 5.6 High-throughput screening (HTS) 170 5.6.1 Biochemical assays 171 5.6.2 Whole cell assays 173 5.6.3 Hits and hit rates 173 5.7 Automatic methods of library generation and analysis 174 5.8 Questions 175 6 Drugs from natural sources 177 6.1 Introduction 177 6.2 Bioassays 179 6.2.1 Screening tests 180 6.2.2 Monitoring tests 183 6.3 Dereplication 185 6.4 Structural analysis of the isolated substance 186 6.5 Active compound development 188 6.6 Extraction procedures 189 6.6.1 General considerations 190 6.6.2 Commonly used methods of extraction 191 6.6.3 Cleaning up procedures 195 6.7 Fractionation methods 195 6.7.1 Liquid–liquid partition 196 6.7.2 Chromatographic methods 199 6.7.3 Precipitation 200 6.7.4 Distillation 200 6.7.5 Dialysis 202 6.7.6 Electrophoresis 202 6.8 Case history: the story of Taxol 202 6.9 Questions 206 7 Biological membranes 207 7.1 Introduction 207 7.2 The plasma membrane 208 7.2.1 Lipid components 209 7.2.2 Protein components 211 7.2.3 The carbohydrate component 213 7.2.4 Similarities and differences between plasma membranes in different cells 213 7.2.5 Cell walls 214 7.2.6 Bacterial cell exterior surfaces 217 7.2.7 Animal cell exterior surfaces 218 7.2.8 Virus 218 7.2.9 Tissue 219 7.2.10 Human skin 219 7.3 The transfer of species through cell membranes 220 7.3.1 Osmosis 220 7.3.2 Filtration 221 7.3.3 Passive diffusion 221 7.3.4 Facilitated diffusion 223 7.3.5 Active transport 223 7.3.6 Endocytosis 224 7.3.7 Exocytosis 225 7.4 Drug action that affects the structure of cell membranes and walls 225 7.4.1 Antifungal agents 226 7.4.2 Antibacterial agents (antibiotics) 230 7.4.3 Local anaesthetics 244 7.5 Questions 249 8 Receptors and messengers 251 8.1 Introduction 251 8.2 The chemical nature of the binding of ligands to receptors 252 8.3 Structure and classification of receptors 254 8.4 General mode of operation 256 8.4.1 Superfamily Type 1 259 8.4.2 Superfamily Type 2 260 8.4.3 Superfamily Type 3 263 8.4.4 Superfamily Type 4 264 8.5 Ligand–response relationships 265 8.5.1 Experimental determination of ligand concentration–response curves 266 8.5.2 Agonist concentration–response relationships 267 8.5.3 Antagonist concentration–receptor relationships 268 8.5.4 Partial agonists 271 8.5.5 Desensitisation 272 8.6 Ligand–receptor theories 272 8.6.1 Clark’s occupancy theory 272 8.6.2 The rate theory 277 8.6.3 The two-state model 278 8.7 Drug action and design 279 8.7.1 Agonists 279 8.7.2 Antagonists 281 8.7.3 Citalopram, an antagonist antidepressant discovered by a rational approach 282 8.7.4 b-Blockers 285 8.8 Questions 289 9 Enzymes 291 9.1 Introduction 291 9.2 Classification and nomenclature 293 9.3 Active sites and catalytic action 295 9.3.1 Allosteric activation 297 9.4 Regulation of enzyme activity 298 9.4.1 Covalent modification 298 9.4.2 Allosteric control 298 9.4.3 Proenzyme control 300 9.5 The specific nature of enzyme action 300 9.6 The mechanisms of enzyme action 302 9.7 The general physical factors affecting enzyme action 302 9.8 Enzyme kinetics 303 9.8.1 Single substrate reactions 303 9.8.2 Multiple substrate reactions 305 9.9 Enzyme inhibitors 306 9.9.1 Reversible inhibitors 307 9.9.2 Irreversible inhibition 312 9.10 Transition state inhibitors 318 9.11 Enzymes and drug design: some general considerations 320 9.12 Examples of drugs used as enzyme inhibitors 321 9.12.1 Sulphonamides 321 9.12.2 Captopril and related drugs 323 9.12.3 Statins 326 9.13 Enzymes and drug resistance 329 9.13.1 Changes in enzyme concentration 330 9.13.2 An increase in the production of the substrate 331 9.13.3 Changes in the structure of the enzyme 331 9.13.4 The use of an alternative metabolic pathway 332 9.14 Ribozymes 332 9.15 Questions 332 10 Nucleic acids 335 10.1 Introduction 335 10.2 Deoxyribonucleic acid (DNA) 336 10.2.1 Structure 337 10.3 The general functions of DNA 338 10.4 Genes 339 10.5 Replication 340 10.6 Ribonucleic acid (RNA) 341 10.7 Messenger RNA (mRNA) 342 10.8 Transfer RNA (tRNA) 343 10.9 Ribosomal RNA (rRNA) 345 10.10 Protein synthesis 345 10.10.1 Activation 345 10.10.2 Initiation 346 10.10.3 Elongation 347 10.10.4 Termination 348 10.11 Protein synthesis in prokaryotic and eukaryotic cells 348 10.11.1 Prokaryotic cells 348 10.11.2 Eukaryotic cells 350 10.12 Bacterial protein synthesis inhibitors (antimicrobials) 350 10.12.1 Aminoglycosides 351 10.12.2 Chloramphenicol 355 10.12.3 Tetracyclines 356 10.12.4 Macrolides 359 10.12.5 Lincomycins 360 10.13 Drugs that target nucleic acids 362 10.13.1 Antimetabolites 362 10.13.2 Enzyme inhibitors 368 10.13.3 Intercalating agents 372 10.13.4 Alkylating agents 374 10.13.5 Antisense drugs 377 10.13.6 Chain cleaving agents 379 10.14 Viruses 380 10.14.1 Structure and replication 380 10.14.2 Classification 381 10.14.3 Viral diseases 383 10.14.4 Antiviral drugs 384 10.15 Recombinant DNA technology (genetic engineering) 389 10.15.1 Gene cloning 389 10.15.2 Medical applications 392 10.16 Questions 401 11 Pharmacokinetics 403 11.1 Introduction 403 11.1.1 General classification of pharmacokinetic properties 405 11.1.2 Drug regimens 405 11.1.3 The importance of pharmacokinetics in drug discovery 406 11.2 Drug concentration analysis and its therapeutic significance 407 11.3 Pharmacokinetic models 409 11.4 Intravascular administration 411 11.4.1 Distribution 412 11.5 Extravascular administration 425 11.5.1 Dissolution 428 11.5.2 Absorption 429 11.5.3 Single oral dose 430 11.5.4 The calculation of tmax and Cmax 433 11.5.5 Repeated oral doses 434 11.6 The use of pharmacokinetics in drug design 435 11.7 Extrapolation of animal experiments to humans 435 11.8 Questions 436 12 Drug metabolism 439 12.1 Introduction 439 12.1.1 The stereochemistry of drug metabolism 439 12.1.2 Biological factors affecting metabolism 440 12.1.3 Environmental factors affecting metabolism 443 12.1.4 Species and metabolism 443 12.1.5 Enzymes and metabolism 443 12.2 Secondary pharmacological implications of metabolism 443 12.2.1 Inactive metabolites 444 12.2.2 Metabolites with a similar activity to the drug 444 12.2.3 Metabolites with a dissimilar activity to the drug 444 12.2.4 Toxic metabolites 445 12.3 Sites of action 445 12.4 Phase I metabolic reactions 446 12.4.1 Oxidation 446 12.4.2 Reduction 448 12.4.3 Hydrolysis 448 12.4.4 Hydration 449 12.4.5 Other Phase I reactions 449 12.5 Examples of Phase I metabolic reactions 449 12.6 Phase II metabolic routes 454 12.7 Pharmacokinetics of metabolites 457 12.8 Drug metabolism and drug design 458 12.9 Prodrugs 460 12.9.1 Bioprecursor prodrugs 461 12.9.2 Carrier prodrugs 462 12.9.3 Photoactivated prodrugs 464 12.9.4 The design of carrier prodrug systems for specific purposes 465 12.10 Questions 475 13 Complexes and chelating agents 477 13.1 Introduction 477 13.2 The shapes and structures of complexes 478 13.2.1 Ligands 479 13.2.2 Bridging ligands 483 13.2.3 Metal–metal bonds 483 13.2.4 Metal clusters 483 13.3 Metal–ligand affinities 485 13.3.1 Affinity and equilibrium constants 485 13.3.2 Hard and soft acids and bases 487 13.3.3 The general medical significance of complex stability 488 13.4 The general roles of metal complexes in biological processes 488 13.5 Therapeutic uses 491 13.5.1 Metal poisoning 491 13.5.2 Anticancer agents 494 13.5.3 Antiarthritics 497 13.5.4 Antimicrobial complexes 498 13.5.5 Photoactivated metal complexes 499 13.6 Drug action and metal chelation 501 13.7 Questions 501 14 Nitric oxide 503 14.1 Introduction 503 14.2 The structure of nitric oxide 503 14.3 The chemical properties of nitric oxide 504 14.3.1 Oxidation 505 14.3.2 Salt formation 506 14.3.3 Reaction as an electrophile 507 14.3.4 Reaction as an oxidising agent 507 14.3.5 Complex formation 508 14.3.6 Nitric oxide complexes with iron 508 14.3.7 The chemical properties of nitric oxide complexes 510 14.3.8 The chemistry of related compounds 512 14.4 The cellular production and role of nitric oxide 514 14.4.1 General mode of action 516 14.4.2 Suitability of nitric oxide as a chemical messenger 518 14.4.3 Metabolism 518 14.5 The role of nitric oxide in physiological and pathophysiological states 519 14.5.1 The role of nitric oxide in the cardiovascular system 519 14.5.2 The role of nitric oxide in the nervous system 520 14.5.3 Nitric oxide and diabetes 522 14.5.4 Nitric oxide and impotence 522 14.5.5 Nitric oxide and the immune system 523 14.6 Therapeutic possibilities 524 14.6.1 Compounds that reduce nitric oxide generation 524 14.6.2 Compounds that supply nitric oxide 526 14.6.3 The genetic approach 529 14.7 Questions 529 15 An introduction to drug and analogue synthesis 531 15.1 Introduction 531 15.2 Some general considerations 532 15.2.1 Starting materials 532 15.2.2 Practical considerations 532 15.2.3 The overall design 532 15.2.4 The use of protecting groups 533 15.3 Asymmetry in syntheses 534 15.3.1 The use of non-stereoselective reactions to produce stereospecific centres 535 15.3.2 The use of stereoselective reactions to produce stereogenetic centres 535 15.3.3 General methods of asymmetric synthesis 541 15.3.4 Methods of assessing the purity of stereoisomers 547 15.4 Designing organic syntheses 548 15.4.1 An introduction to the disconnection approach 548 15.4.2 Convergent synthesis 554 15.5 Partial organic synthesis of xenobiotics 556 15.6 Questions 557 16 Drug development and production 559 16.1 Introduction 559 16.2 Chemical development 560 16.2.1 Chemical engineering issues 561 16.2.2 Chemical plant: health and safety considerations 562 16.2.3 Synthesis quality control 563 16.2.4 A case study 563 16.3 Pharmacological and toxicological testing 565 16.4 Drug metabolism and pharmacokinetics 569 16.5 Formulation development 570 16.6 Production and quality control 570 16.7 Patent protection 571 16.8 Regulation 572 16.9 Questions 573 Selected further reading 575 Answers to questions 579 Index 601

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Book SynopsisWritten in an accessible style, Medicinal Chemistry: An Introduction, Second Edition carefully explains fundamental principles of the subject while assuming little in the way of prior knowledge. The book focuses on the chemical principles used for drug discovery and design covering physiology and biology where relevant.Table of ContentsPreface to the First Edition xv Preface to the Second Edition xvii Acknowledgements xix Abbreviations xxi 1 An introduction to drugs, their action and discovery 1 1.1 Introduction 1 1.2 What are drugs and why do we need new ones? 1 1.3 Drug discovery and design: a historical outline 3 1.3.1 The general stages in modern-day drug discovery and design 7 1.4 Leads and analogues: some desirable properties 9 1.4.1 Bioavailability 9 1.4.2 Solubility 10 1.4.3 Structure 10 1.4.4 Stability 11 1.5 Sources of leads and drugs 14 1.5.1 Ethnopharmaceutical sources 15 1.5.2 Plant sources 15 1.5.3 Marine sources 17 1.5.4 Microorganisms 18 1.5.5 Animal sources 20 1.5.6 Compound collections, data bases and synthesis 20 1.5.7 The pathology of the diseased state 21 1.5.8 Market forces and ‘me-too drugs’ 21 1.6 Methods and routes of administration: the pharmaceutical phase 21 1.7 Introduction to drug action 24 1.7.1 The pharmacokinetic phase (ADME) 25 1.7.2 The pharmacodynamic phase 32 1.8 Classification of drugs 33 1.8.1 Chemical structure 33 1.8.2 Pharmacological action 34 1.8.3 Physiological classification 34 1.8.4 Prodrugs 35 1.9 Questions 35 2 Drug structure and solubility 37 2.1 Introduction 37 2.2 Structure37 2.3 Stereochemistry and drug design 38 2.3.1 Structurally rigid groups 38 2.3.2 Conformation 39 2.3.3 Configuration 41 2.4 Solubility 44 2.4.1 Solubility and the physical nature of the solute 44 2.5 Solutions 46 2.6 The importance of water solubility 47 2.7 Solubility and the structure of the solute 49 2.8 Salt formation 50 2.9 The incorporation of water solubilising groups in a structure 52 2.9.1 The type of group 52 2.9.2 Reversible and irreversible groups 53 2.9.3 The position of the water solubilising group 53 2.9.4 Methods of introduction 54 2.9.5 Improving lipid solubility 59 2.10 Formulation methods of improving water solubility 59 2.10.1 Cosolvents 59 2.10.2 Colloidal solutions 59 2.10.3 Emulsions 60 2.11 The effect of pH on the solubility of acidic and basic drugs 61 2.12 Partition 63 2.12.1 Practical determination of partition coefficients 65 2.12.2 Theoretical determination of partition coefficients 66 2.13 Surfactants and amphiphiles 66 2.13.1 Drug solubilisation 69 2.13.2 Mixed micelles as drug delivery systems 71 2.13.3 Vesicles and liposomes 72 2.14 Questions 72 3 Structure–activity and quantitative structure relationships 75 3.1 Introduction 75 3.2 Structure–activity relationship (SAR) 76 3.3 Changing size and shape 77 3.3.1 Changing the number of methylene groups in chains and rings 77 3.3.2 Changing the degree of unsaturation 78 3.3.3 Introduction or removal of a ring system 78 3.4 Introduction of new substituents 80 3.4.1 Methyl groups 81 3.4.2 Halogen groups 83 3.4.3 Hydroxy groups 84 3.4.4 Basic groups 84 3.4.5 Carboxylic and sulphonic acid groups 85 3.4.6 Thiols, sulphides and other sulphur groups 85 3.5 Changing the existing substituents of a lead 86 3.6 Case study: a SAR investigation to discover potent geminal bisphosphonates 87 3.7 Quantitative structure–activity relationship (QSAR) 90 3.7.1 Regression analysis 93 3.7.2 The lipophilic parameters 94 3.7.3 Electronic parameters 99 3.7.4 Steric parameters 102 3.8 Questions 110 4 Computer-aided drug design 113 4.1 Introduction 113 4.1.1 Models 114 4.1.2 Molecular modelling methods 115 4.1.3 Computer graphics 116 4.2 Molecular mechanics 117 4.2.1 Creating a molecular model using molecular mechanics 120 4.3 Molecular dynamics 123 4.3.1 Conformational analysis 124 4.4 Quantum mechanics 124 4.5 Docking 127 4.5.1 De novo design 128 4.6 Comparing three-dimensional structures by the use of overlays 130 4.6.1 An example of the use of overlays 132 4.7 Pharmacophores and some of their uses 133 4.7.1 High-resolution X-ray crystallography or NMR 133 4.7.2 Analysis of the structures of different ligands 134 4.8 Modelling protein structures 135 4.9 Three-dimensional QSAR 136 4.9.1 Advantages and disadvantages 140 4.10 Other uses of computers in drug discovery 141 4.11 Questions 143 5 Combinatorial chemistry 145 5.1 Introduction 145 5.1.1 The design of combinatorial syntheses 147 5.1.2 The general techniques used in combinatorial synthesis 148 5.2 The solid support method 148 5.2.1 General methods in solid support combinatorial chemistry 150 5.2.2 Parallel synthesis 152 5.2.3 Furka’s mix and split technique 155 5.3 Encoding methods 157 5.3.1 Sequential chemical tagging 157 5.3.2 Still’s binary code tag system 160 5.3.3 Computerised tagging 161 5.4 Combinatorial synthesis in solution 161 5.4.1 Parallel synthesis in solution 162 5.4.2 The formation of libraries of mixtures 163 5.4.3 Libraries formed using monomethyl polyethylene glycol (OMe-PEG) 164 5.4.4 Libraries produced using dendrimers as soluble supports 164 5.4.5 Libraries formed using fluorocarbon reagents 165 5.4.6 Libraries produced using resin-bound scavenging agents 166 5.4.7 Libraries produced using resin-bound reagents 168 5.4.8 Resin capture of products 168 5.5 Deconvolution 169 5.6 High-throughput screening (HTS) 170 5.6.1 Biochemical assays 171 5.6.2 Whole cell assays 173 5.6.3 Hits and hit rates 173 5.7 Automatic methods of library generation and analysis 174 5.8 Questions 175 6 Drugs from natural sources 177 6.1 Introduction 177 6.2 Bioassays 179 6.2.1 Screening tests 180 6.2.2 Monitoring tests 183 6.3 Dereplication 185 6.4 Structural analysis of the isolated substance 186 6.5 Active compound development 188 6.6 Extraction procedures 189 6.6.1 General considerations 190 6.6.2 Commonly used methods of extraction 191 6.6.3 Cleaning up procedures 195 6.7 Fractionation methods 195 6.7.1 Liquid–liquid partition 196 6.7.2 Chromatographic methods 199 6.7.3 Precipitation 200 6.7.4 Distillation 200 6.7.5 Dialysis 202 6.7.6 Electrophoresis 202 6.8 Case history: the story of Taxol 202 6.9 Questions 206 7 Biological membranes 207 7.1 Introduction 207 7.2 The plasma membrane 208 7.2.1 Lipid components 209 7.2.2 Protein components 211 7.2.3 The carbohydrate component 213 7.2.4 Similarities and differences between plasma membranes in different cells 213 7.2.5 Cell walls 214 7.2.6 Bacterial cell exterior surfaces 217 7.2.7 Animal cell exterior surfaces 218 7.2.8 Virus 218 7.2.9 Tissue 219 7.2.10 Human skin 219 7.3 The transfer of species through cell membranes 220 7.3.1 Osmosis 220 7.3.2 Filtration 221 7.3.3 Passive diffusion 221 7.3.4 Facilitated diffusion 223 7.3.5 Active transport 223 7.3.6 Endocytosis 224 7.3.7 Exocytosis 225 7.4 Drug action that affects the structure of cell membranes and walls 225 7.4.1 Antifungal agents 226 7.4.2 Antibacterial agents (antibiotics) 230 7.4.3 Local anaesthetics 244 7.5 Questions 249 8 Receptors and messengers 251 8.1 Introduction 251 8.2 The chemical nature of the binding of ligands to receptors 252 8.3 Structure and classification of receptors 254 8.4 General mode of operation 256 8.4.1 Superfamily Type 1 259 8.4.2 Superfamily Type 2 260 8.4.3 Superfamily Type 3 263 8.4.4 Superfamily Type 4 264 8.5 Ligand–response relationships 265 8.5.1 Experimental determination of ligand concentration–response curves 266 8.5.2 Agonist concentration–response relationships 267 8.5.3 Antagonist concentration–receptor relationships 268 8.5.4 Partial agonists 271 8.5.5 Desensitisation 272 8.6 Ligand–receptor theories 272 8.6.1 Clark’s occupancy theory 272 8.6.2 The rate theory 277 8.6.3 The two-state model 278 8.7 Drug action and design 279 8.7.1 Agonists 279 8.7.2 Antagonists 281 8.7.3 Citalopram, an antagonist antidepressant discovered by a rational approach 282 8.7.4 b-Blockers 285 8.8 Questions 289 9 Enzymes 291 9.1 Introduction 291 9.2 Classification and nomenclature 293 9.3 Active sites and catalytic action 295 9.3.1 Allosteric activation 297 9.4 Regulation of enzyme activity 298 9.4.1 Covalent modification 298 9.4.2 Allosteric control 298 9.4.3 Proenzyme control 300 9.5 The specific nature of enzyme action 300 9.6 The mechanisms of enzyme action 302 9.7 The general physical factors affecting enzyme action 302 9.8 Enzyme kinetics 303 9.8.1 Single substrate reactions 303 9.8.2 Multiple substrate reactions 305 9.9 Enzyme inhibitors 306 9.9.1 Reversible inhibitors 307 9.9.2 Irreversible inhibition 312 9.10 Transition state inhibitors 318 9.11 Enzymes and drug design: some general considerations 320 9.12 Examples of drugs used as enzyme inhibitors 321 9.12.1 Sulphonamides 321 9.12.2 Captopril and related drugs 323 9.12.3 Statins 326 9.13 Enzymes and drug resistance 329 9.13.1 Changes in enzyme concentration 330 9.13.2 An increase in the production of the substrate 331 9.13.3 Changes in the structure of the enzyme 331 9.13.4 The use of an alternative metabolic pathway 332 9.14 Ribozymes 332 9.15 Questions 332 10 Nucleic acids 335 10.1 Introduction 335 10.2 Deoxyribonucleic acid (DNA) 336 10.2.1 Structure 337 10.3 The general functions of DNA 338 10.4 Genes 339 10.5 Replication 340 10.6 Ribonucleic acid (RNA) 341 10.7 Messenger RNA (mRNA) 342 10.8 Transfer RNA (tRNA) 343 10.9 Ribosomal RNA (rRNA) 345 10.10 Protein synthesis 345 10.10.1 Activation 345 10.10.2 Initiation 346 10.10.3 Elongation 347 10.10.4 Termination 348 10.11 Protein synthesis in prokaryotic and eukaryotic cells 348 10.11.1 Prokaryotic cells 348 10.11.2 Eukaryotic cells 350 10.12 Bacterial protein synthesis inhibitors (antimicrobials) 350 10.12.1 Aminoglycosides 351 10.12.2 Chloramphenicol 355 10.12.3 Tetracyclines 356 10.12.4 Macrolides 359 10.12.5 Lincomycins 360 10.13 Drugs that target nucleic acids 362 10.13.1 Antimetabolites 362 10.13.2 Enzyme inhibitors 368 10.13.3 Intercalating agents 372 10.13.4 Alkylating agents 374 10.13.5 Antisense drugs 377 10.13.6 Chain cleaving agents 379 10.14 Viruses 380 10.14.1 Structure and replication 380 10.14.2 Classification 381 10.14.3 Viral diseases 383 10.14.4 Antiviral drugs 384 10.15 Recombinant DNA technology (genetic engineering) 389 10.15.1 Gene cloning 389 10.15.2 Medical applications 392 10.16 Questions 401 11 Pharmacokinetics 403 11.1 Introduction 403 11.1.1 General classification of pharmacokinetic properties 405 11.1.2 Drug regimens 405 11.1.3 The importance of pharmacokinetics in drug discovery 406 11.2 Drug concentration analysis and its therapeutic significance 407 11.3 Pharmacokinetic models 409 11.4 Intravascular administration 411 11.4.1 Distribution 412 11.5 Extravascular administration 425 11.5.1 Dissolution 428 11.5.2 Absorption 429 11.5.3 Single oral dose 430 11.5.4 The calculation of tmax and Cmax 433 11.5.5 Repeated oral doses 434 11.6 The use of pharmacokinetics in drug design 435 11.7 Extrapolation of animal experiments to humans 435 11.8 Questions 436 12 Drug metabolism 439 12.1 Introduction 439 12.1.1 The stereochemistry of drug metabolism 439 12.1.2 Biological factors affecting metabolism 440 12.1.3 Environmental factors affecting metabolism 443 12.1.4 Species and metabolism 443 12.1.5 Enzymes and metabolism 443 12.2 Secondary pharmacological implications of metabolism 443 12.2.1 Inactive metabolites 444 12.2.2 Metabolites with a similar activity to the drug 444 12.2.3 Metabolites with a dissimilar activity to the drug 444 12.2.4 Toxic metabolites 445 12.3 Sites of action 445 12.4 Phase I metabolic reactions 446 12.4.1 Oxidation 446 12.4.2 Reduction 448 12.4.3 Hydrolysis 448 12.4.4 Hydration 449 12.4.5 Other Phase I reactions 449 12.5 Examples of Phase I metabolic reactions 449 12.6 Phase II metabolic routes 454 12.7 Pharmacokinetics of metabolites 457 12.8 Drug metabolism and drug design 458 12.9 Prodrugs 460 12.9.1 Bioprecursor prodrugs 461 12.9.2 Carrier prodrugs 462 12.9.3 Photoactivated prodrugs 464 12.9.4 The design of carrier prodrug systems for specific purposes 465 12.10 Questions 475 13 Complexes and chelating agents 477 13.1 Introduction 477 13.2 The shapes and structures of complexes 478 13.2.1 Ligands 479 13.2.2 Bridging ligands 483 13.2.3 Metal–metal bonds 483 13.2.4 Metal clusters 483 13.3 Metal–ligand affinities 485 13.3.1 Affinity and equilibrium constants 485 13.3.2 Hard and soft acids and bases 487 13.3.3 The general medical significance of complex stability 488 13.4 The general roles of metal complexes in biological processes 488 13.5 Therapeutic uses 491 13.5.1 Metal poisoning 491 13.5.2 Anticancer agents 494 13.5.3 Antiarthritics 497 13.5.4 Antimicrobial complexes 498 13.5.5 Photoactivated metal complexes 499 13.6 Drug action and metal chelation 501 13.7 Questions 501 14 Nitric oxide 503 14.1 Introduction 503 14.2 The structure of nitric oxide 503 14.3 The chemical properties of nitric oxide 504 14.3.1 Oxidation 505 14.3.2 Salt formation 506 14.3.3 Reaction as an electrophile 507 14.3.4 Reaction as an oxidising agent 507 14.3.5 Complex formation 508 14.3.6 Nitric oxide complexes with iron 508 14.3.7 The chemical properties of nitric oxide complexes 510 14.3.8 The chemistry of related compounds 512 14.4 The cellular production and role of nitric oxide 514 14.4.1 General mode of action 516 14.4.2 Suitability of nitric oxide as a chemical messenger 518 14.4.3 Metabolism 518 14.5 The role of nitric oxide in physiological and pathophysiological states 519 14.5.1 The role of nitric oxide in the cardiovascular system 519 14.5.2 The role of nitric oxide in the nervous system 520 14.5.3 Nitric oxide and diabetes 522 14.5.4 Nitric oxide and impotence 522 14.5.5 Nitric oxide and the immune system 523 14.6 Therapeutic possibilities 524 14.6.1 Compounds that reduce nitric oxide generation 524 14.6.2 Compounds that supply nitric oxide 526 14.6.3 The genetic approach 529 14.7 Questions 529 15 An introduction to drug and analogue synthesis 531 15.1 Introduction 531 15.2 Some general considerations 532 15.2.1 Starting materials 532 15.2.2 Practical considerations 532 15.2.3 The overall design 532 15.2.4 The use of protecting groups 533 15.3 Asymmetry in syntheses 534 15.3.1 The use of non-stereoselective reactions to produce stereospecific centres 535 15.3.2 The use of stereoselective reactions to produce stereogenetic centres 535 15.3.3 General methods of asymmetric synthesis 541 15.3.4 Methods of assessing the purity of stereoisomers 547 15.4 Designing organic syntheses 548 15.4.1 An introduction to the disconnection approach 548 15.4.2 Convergent synthesis 554 15.5 Partial organic synthesis of xenobiotics 556 15.6 Questions 557 16 Drug development and production 559 16.1 Introduction 559 16.2 Chemical development 560 16.2.1 Chemical engineering issues 561 16.2.2 Chemical plant: health and safety considerations 562 16.2.3 Synthesis quality control 563 16.2.4 A case study 563 16.3 Pharmacological and toxicological testing 565 16.4 Drug metabolism and pharmacokinetics 569 16.5 Formulation development 570 16.6 Production and quality control 570 16.7 Patent protection 571 16.8 Regulation 572 16.9 Questions 573 Selected further reading 575 Answers to questions 579 Index 601

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Book SynopsisFragment-based drug discovery (FBDD) is a new paradigm in drug discovery that utilizes very small molecules - fragments of larger molecules. It is a faster, cheaper, smarter way to do drug discovery, as shown by the number of pharmaceutical companies that have embraced this approach and the biotechnology companies who use fragments as their sole source of drug discovery. Fragment-Based Drug Discovery: A Practical Approach is a guide to the techniques and practice of using fragments in drug screening. The emphasis is on practical guidance, with procedures, case studies, practical tips, and contributions from industry. Topics covered include: an introduction to fragment based drug discovery, why using fragments is a more efficient process than predominant models, and what it means to have a successful FBDD effort. setting up an FBDD project library building and production NMR in fragment screening and follow up Trade Review"This is a useful book for readers already familiar with the basic aspects of drug design and discovery." (ChemMedChem, October 2009) "This book provides an excellent resource for those in pharmaceutical research who are interested in fragment-based drug discovery. Most of the topics are covered in enough detail that this book could be used as a guide for those initiating a program in fragment-based drug discovery." (Journal of the American Chemical Society, April 29, 2009) "As the authors eloquently state in Chapter 2, 'Where there is a validated target and a will, there is a (drug discovery) way.'" (Journal of Medicinal Chemistry, 2009) Table of Contents1. Introduction to Fragment based Drug Discovery (Tim Mitchell and Mike Cherry). 2. Building the Perfect Beast: Designing a Fragment Process to Fit Your Needs (Edward Zartler and Michael Shapiro). 3. Assembling a Fragment Library (Mark Brewer, Osamu Ichihara, Christian Kirchhoff, Markus Schade, and Mark Whittaker). 4. The Practical Aspects of Using NMR in Fragment Based Screening (Johan Schultz). 5. Application of Protein-Ligand NOE Matching to the Rapid Evaluation of Fragment Binding Poses (William J. Metzler, Brian L. Claus, Patricia McDonnell, Stephen R. Johnson, Valentina Goldfarb, Malcolm E. Davis, Luciano Mueller, and Keith L. Constantine). 6. Target Immobilized NMR Screening: Validation and Extension to Membrane Proteins (Virginie Früh, Robert J. Heetebrij and Gregg Siegal). 7. In situ fragment-based medicinal chemistry: screening by mass spectrometry (Sally-Ann Poulsen and Gary H. Kruppa). 8. Computational approaches to fragment and substructure discovery and evaluation (Eelke van der Horst and Adriaan P. IJzerman). 9. In Silico Design Chapter (Bradley Feuston, M. Katharine Holloway, Georgia McGaughey and J. Chris Culberson). 10. Fragment-based lead discovery using covalent capture methods (Stig K. Hansen and Daniel A. Erlanson). 11. Identification of high affinity beta-secretase inhibitors using fragment-based lead generation. Jeffrey S. Albert and Philip D. Edwards.

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Book SynopsisProviding an updated and expert overview of nuclear hormone receptors in drug metabolism and drug development, this book equips drug development scientists with an interdisciplinary understanding of these receptors and how to regulate them.Table of ContentsPreface. Abbreviations. Contributors. Chapter 1. Drug Metabolism: Significance and Challenges (Chandra Prakash and Alfin D.N. Vaz). 1.1. Introduction. 1.2. Phase I Drug Metabolizing Enzymes. 1.3. Phase II Conjugative Enzymes. 1.4. Drug Efflux Transporters. 1.5. Drug Uptake Transporters. 1.6. Challenges in Drug Metabolism. 1.7. Summary. 1.8. References. Chapter 2. Establishing Orphan Nuclear Receptors PXR and CAR as Xenobiotic Receptors (Tao Li, Junichiro Sonoda, and Ronald M. Evans). 2.1. Introduction. 2.2. Nuclear Receptor and Orphan Nuclear Receptor Superfamily. 2.3. Orphan Nuclear Receptors as Xenobiotic Receptors and Their Implications in Phase I Enzyme Regulation. 2.4. Perspectives. 2.5. References. Chapter 3. Nuclear Receptor-Mediated Regulation of Phase II Conjugating Enzymes (Olivier Barbier). 3.1. Introduction. 3.2. Phase II Drug Metabolizing Enzymes. 3.3. The Xenosensors CAR and PXR: 2 Masters Regulators of Phase II Metabolism. 3.4. AhR And Nrf2, Two Important Regulators of Phase II Enzymes. 3.5. PPARS and Phase II XMEs Regulation. 3.6. FXR/LXR and Phase II XMEs Regulation. 3.7. HNF and Phase II XMEs Regulation. 3.8. Regulation of Phase II Conjugating Enzymes by Steroid and Thyroid Receptors. 3.9. Concluding remarks and perspectives. 3.10. References. Chapter 4. Nuclear Receptor-Mediated Regulation of Drug Transporters (Oliver Burk). 4.1. Introduction. 4.2. Drug Transporters. 4.3. Induction of Drug Transporters by Activation of PXR and CAR. 4.4. Induction of Drug Transporters by Activation of PPARa. 4.5. Molecular Mechanism of PXR- and CAR-Dependent Drug Transporter Regulation. 4.6. Induction of Drug Transporter Expression and Drug Disposition. 4.7. Conclusions and Future Perspectives. 4.8. References. Chapter 5. Structure and Function of PXR and CAR (X. Edward Zhou and H. Eric Xu). 5.1. Introduction. 5.2. Structure and Function of PXR. 5.3. Structure and Function of CAR. 5.4. Concluding Remarks. 5.5. References. Chapter 6. Xenobiotic Receptor CoFactors and Coregulators (John Y. L. Chiang). 6.1. Regulation of PXR and CAR Nuclear Translocation. 6.2. Nuclear Receptor Coregulators and Epigenetic Regulation of Gene Transcription. 6.3. PXR and CAR Crosstalk with other Nuclear Receptors and Transcription Factors. 6.4. PXR and CAR Regulation of Lipid and Glucose Homeostasis. 6.5. Conclusion. 6.6. References. Chapter 7. Animal Models of Xenobiotic Nuclear Receptors and Their Utility in Drug Development (Haibiao Gong and Wen Xie). 7.1. Introduction. 7.2. PXR and CAR Loss-of-Function (Knock Out) Mouse Models. 7.3. PXR and CAR Gain-of-Function (Transgenic) Mouse Models. 7.4. Humanized Mouse Models. 7.5. Utility of Xenobiotic Mouse Models in Pharmaceutical Development. 7.6. Closing Remarks. 7.7. References. Chapter 8. Nuclear Receptors and Drug-Drug Interactions with Prescription Drugs and Herbal Medicines (Rommel G. Tirona and Richard B. Kim). 8.1. Introduction. 8.2. Prescription Drugs/Drug Classes Commonly Involved in Inductive Interactions. 8.3. Herbal Drug Medicines Commonly Involved in Inductive Interactions. 8.4. Pharmacology of Induction. 8.5. Clinical Aspects of Induction-Type Drug Interactions. 8.6. Inhibition of Nuclear Receptors in Clinical Drug Interactions. 8.7. Nuclear Receptor-Mediated Drug Side-Effects. 8.8. Perspectives. 8.9. References. Chapter 9. Genetic Variants of Xenobiotic Receptors and Their Implications in Drug Metabolism and Pharmacogenetics (Jatinder Lamba and Erin G. Schuetz). 9.1. PXR (Pregnane X Receptor) Background. 9.2. PXR Gene Structure. 9.3. PXR Alternative mRNAs. 9.4. Genetic Variants in PXR’s Exons and their Functional Consequences. 9.5. Genetic Variants In Introns 2-8 and the 3’-UTR of PXR and their Functional Consequences. 9.6. Resequencing Strategy for the PXR Promoter and Intron 1. 9.7. Genetic Variation in the PXR Promoter and 5’-UTR and its Functional Relevance. 9.8. Genetic Variation in PXR’s Intron 1 and its Functional Relevance. 9.9. In Silico Analysis for Functional Effect of SNPs in PXR’s Promoter, 5’-UTR and Intron 1. 9.10. SNPs in PXR’s Promoter and Intron 1 Affect Putative HNF Binding Sites. 9.11. PXR SNPs Have Been Associated with Intestinal and Hepatic Inflammation and Diseases. 9.12. PXR Structural Variation and other Genomic Features. 9.13. PXR Summary. 9.14. CAR-Background. 9.15. CAR Gene Structure. 9.16. CAR Alternatively Spliced RNAs. 9.17. CAR Genetic Variants (SNPs) and their Functional Consequences. 9.18. CAR Summary. 9.19. References. Chapter 10. Beyond PXR and CAR, Regulation of Xenobiotic Metabolism by Other Nuclear Receptors (Martin Wagner, Gernot Zollner, and Michael Trauner). 10.1. Introduction. 10.2. Farnesoid X Receptor. 10.3. Hepatocyte Nuclear Factor 4. 10.4. Vitamin D receptor. 10.5. Glucocorticoid Receptor. 10.6. Peroxisome Proliferator Activated Receptors. 10.7. Aryl Hydrocarbon Receptor (AhR). 10.8. Conclusions. 10.9. References. Chapter 11. Emerging Role of Retinoid-Related Orphan Receptor (ROR) and Its Crosst alk With LXR(Liver X Receptor) in the Regulation Of Drug-Metabolizing Enzymes (Taira Wada and Wen Xie). 11.1. Introduction. 11.2. Orphan Nuclear Receptor RORα. 11.3. A Potential Role of RORs in Xeno- and Endobiotic Gene Regulation. 11.4. LXR and its Regulation of Drug Metabolizing Enzymes. 11.5. A Functional Cross-Talk Between RORa and LXR in the Regulation of Xeno- and Endobiotic Genes. 11.6. Closing Remarks. Index.

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Book SynopsisThis book introduces drug researchers to the novel computational approaches of pathway analysis and explains the existing applications that can save time and money in the drug discovery process. It covers traditional computational methods and software for pathway analysis microarray, proteomics, and metabolomics.Trade Review"Pathway analysis will help lead to a better understanding of the chemistry of living systems and the aberrations that disrupt health. This new book will serve as a beacon to research interested in this field." (Journal of Medicinal Chemistry, April 9, 2009)Table of ContentsPreface. Contributors. 1 Introduction to Pathway Analysis (Anton Yuryev). 2 Software Infrastructure and Data Model for Pathway Analysis (Fedor Bokov and Anton Yuryev). 3 Automatic Pathway Inference in Heterogeneous Biological Association Networks (Anton Yuryev, Andrey Kalinin, and Nikolai Daraselia). 4 Algorithmic Basis for Pathway Visualization (Sergey Simakov, Iaroslav Ispolatov, Sergei Maslov, and Alexander Nikitin). 5 Pathway Analysis of High-Throughput Experimental Data (Andrey Y. Sivachenko). 6 Integrative Pathway Analysis of Disease Molecular Data (Andrej Bugrim, Zoltan Dezso, Yuri Nikolsky, and Tatiana Nikolskaya). 7 Whole-Genome Expression Profi ling of Papillary Serous Ovarian Cancer: Activated Pathways, Potential Targets, and Noise (John Farley, Laurent L. Ozbun, and Michael J. Birrer). 8 Mammalian Proteome and Toxicant Network Analysis (Sean Ekins and Craig N. Giroux). 9 Unraveling Mechanisms of Toxicity with the Power of Pathways: ToxWiz Tool as an Illustrative Example (Mark P. Kühnel, Bojana Cosovic, Goran Medic, Robert B. Russell, and Gordana Apic). 10 Impact of Chemistry Information on Pathway Analysis (Sreenivas Devidas). 11 Propagation of Concentration Perturbations in Equilibrium Protein Binding Networks (Sergei Maslov and Iaroslav Ispolatov). 12 An Adaptive System Model of the Yeast Glucose Sensor System (Todor Vujasinovic and André Siniša Žampera). 13 Present and Future of Pathway Analysis in Drug Discovery (Anton Yuryev). Index.

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Book SynopsisThis is the definitive, one-stop resource on preclinical drug evaluation for potential mitochondrial toxicity, addressing the issue upfront in the drug development process. It discusses mitochondrial impairment to organs, skeletal muscle, and nervous systems and details methodologies used to assess mitochondria function. It covers both in vitro and in vivo methods for analysis and includes the latest models. This is the authoritative reference on drug-induced mitochondrial dysfunction for safety assessment professionals in the pharmaceutical industry and for pharmacologists and toxicologists in both drug and environmental health sciences.Table of ContentsContributors. Preface. Part I: Basic Concepts. 1. Basic Mitochondrial Physiology in Cell Viability and Death (Lech Wojtczak and Krzysztof Zabtocki). 2. Basic Molecular Biology of Mitochondrial Replication (Immo E. Scheffler). 3. Drug-Associated Mitochondrial Toxicity (Rhea Mehta, Katie Chan, Owen Lee, Shahrzad Tafazoli, and Peter J. O'Brien). 4. Pharmacogenetics of Mitochondrial Drug Toxicity (Neil Howell and Corinna Howell). Part II: Organ Drug Toxicity: Mitochondrial Etiology. 5. Features and Mechanisms of Drug-Induced Liver Injury (Dominique Pessayre, Alain Berson, and Bernard Fromenty). 6. Cardiovascular Toxicity of Mitochondrial Origin (Paulo J. Oliveira, Vilma A. Saradao, and Kendall B. Wallace). 7. Skeletal Muscle and Mitochondrial toxicity (Timothy E. Johnson). 8. Manifestations of Drug Toxicity on Mitochondria in the Nervous System (Ian J. Reynolds). 9. Lipoatrophy and Other Manifestations of Antiretroviral Therapeutics (Ulrich A. Walker). 10. Nephrotoxocity (Alberto Ortiz, Alberto Tejedor, and Carlos Caramelo). 11. Drug Effects in Patients with Mitochondrial Diseases (Eric A. Schon, Michio Hirano, and Salvatore DiMauro). Part III: Assessment of Mitochondrial Function in Vitro and In Vivo. 12. Polarographic Oxygen Sensors, the Oxygraph, and High-Resolution Respirometry to Assess Mitochondrial Function (Erich Gnaiger). 13. Use of Oxygen-Sensitive Fluorescent Probes for the Assesment of Mitochondrial Function (James Hynes, Tomas C. O'riordan, and Dmitri B. Papkovsky). 14. Mitochondrial Dysfunction Assessed Quantitatively in Real Time by Measuring the Extracellular Flux of Oxygen and Protons (David Ferrick, Min Wu, Amy Swift, and Andy Neilson). 15. Assessment of Mitochondrial Respiratory Complex Function In Vitro and In Vivo (Mark A. Birch -Machin). 16. OXPHOS Complex Activity Assays and Dipstick Immunoassays for Assessment of OXPHOS Protein Levels (Sashi Nadanaciva). 17. Use of Fluorescent Reporters to Measure Mitochondrial Membrane Potential and the Mitochondrial Permeability Transition (Anna Liisa Nieminen, Benkat K. Ramshesh, and John L. Lemasters). 18. Compartmentation of Redox Signaling and Control: Discrimination of Oxidative Stress in Mitochondria, Cytoplasm, Nuclei, and endoplasmic Reticulum (Patrick J. Halvey, Jason M. Hansen, Lawrence H. Lash, and Dean P. Hones). 19. Assessing Mitochondrial Protein Synthesis in Drug Toxicity Screening (Edward E. McKee). 20. Mitochondrial Toxicity of Antiviral Drugs: A Challenge to Accurate Diagnosis (Michel P. de Baar and Anthony de Ronde). 21. Clinical Assessment of Mitochondrial Function via [13C]Methionine Exhalation (Laura Milazzo). 22. Assessment of Mitochondrial Dysfunction by Microscopy (Ingrid Pruimboom-Brees, Germaine Boucher, Amy Jakowski, and Jeanne Wolfgang). 23. Development of Animal Models of Drug-Induced Mitochondrial Toxicity (Urs A. Boelsterli and Yie Hou Lee). 24. Noninvasive Assessment of Mitochondrial Function Using Nuclear Magnetic Resonance Spectroscopy (Robert W. Wiseman and J.A. L. Jeneson). 25. Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations (Michael P. Murphy). Index.

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Book SynopsisThis book examines and evaluates the strategies utilized to design and synthesize pharmaceutically active agents. Significant updates over the last 10 years since the publication of the 1st edition include synthesis of enantiomerically pure isomers, novel chemical methodologies, and new pharmaceutical agents targeted at novel biological endpoints. Written by an experienced successful author, this book meets the needs of a growing community of researchers in pharmaceutical R &D, as well as medical professionals, by providing a useful guide for designing and synthesizing pharmaceutical agents. Additionally, it is a useful text for medicinal chemistry students.Trade Review?In this book, Lednicer presents a detailed discussion of strategies toward the synthesis of pharmaceutical compounds. . . The strength of the book is the wealth of data collected in one relatively short tone?.Table of ContentsPreface 1. PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS. 1.1 Prostaglandnis. 1.2 Peptidonimetic Compounds. 1.3 Retinoids. 1.4 A Miscellaneous Drug. References. 2. DRUG BASED ON A SUBSTITUTED BENZENE RING 2.1 Arylethanolamines. 2.2 Aryloxypropanolamines. 2.3 Arylsulfonic Acid Derivatives. 2.4 Arylacetic and Arylpropionic Acids. 3. INDENES, NAPHTHALENES AND OTHER POLYCYCLIC AROMATIC COMPOUNDS 3.1 Indenes. 3.2 Naphthalenes. 3.3 Partly Reduced Naphthalenes. 3.4 Tricyclic Compounds. References. 4. STEROIDS; PART 1: ESTRANES, GONANES, AND ANDROSTANES 4.1 Introduction. 4.2 Steroid Starting Materials. 4.3 Estranes. 4.4 Gonanes, the 19-nor Steroids. 4.5 Androstanes. References. 5. STEROIDS; PART 2: COMPOUNDS RELATED TO PROGESTERONE, CORTISONE, AND CHOLESTEROL. 5.1 Introduction. 5.2 Progestins. 5.3 Corticosteroids. 5.4 Compounds Derived from Cholesterol. References. 6. NONSTEROIDAL SEX HORMONES AND THEIR ANTAGONISTS 6.1 Introduction. 6.2 Estrogens. References. 7. OPIOID ANAlGESICS 7.1 Introduction 7.2 Drugs Derived from Morphine. 7.3 Compounds Prepared from Thebaine. 7.4 Morphinans. 7.5 Benzomorphans. 7.6 Analgesics Based on Nonfused Piperidines. References. 8. DRUGS BASED ON FIVE-MEMBERED HETEROCYCLES 8.1 Introduction. 8.2 Rings that Contain One Heteroatom. 8.3 Rings that Contain Two Heteroatoms. 8.4 Rings that Contains Three or More Heteroatoms. References. 9. DRUGS BASED ON SIX-MEMBERED HETEROCYCLES. 9.1 Rings that Contain One Heteroatom. 9.2 Rings that Contain Two Heteroatoms. 9.3 Rings Containing Three Heteroatoms: The Triazines. References. 10. FIVE-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING. 10.1 Compounds that Contain One Heteroatom. 10.2 Compounds that Contain Two Heteroatoms. 10.3 Compounds that Contain Three Heteroatoms. References. 11. SIX-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING 11.1 Compounds that Contain One Heteroatom. 11.2 Compounds that Contain Two Heteroatoms. 11.3 Compounds that Contain Three Heteroatoms. References. 12. SEVEN-MEMBERED HETEROCYCLIC FUSED TO BENZENE. 12.1 Compounds with a Single Heterocyclic Atom. 12.2 Compounds with Two Heteroatoms. References. 13. HETEROCYLES FUSED TO TWO AROMATIC RINGS 13.1 Compounds Containing a Single Heteroatom. 13.2 Compounds Containing Two Heteroatoms. 13.3 Pyridine-Based Fused Tricyclic Compounds. References. 14. BETA LACTAM ANTIBIOTICS 14.1 Penicillins. 14.2 Cephalosporins. 14.3 Monobactams. References. 15. HETEROCYCLES FUSED TO OTHER HETEROCYCLIC RINGS. 15.1 Two Fused Five-Membered Rings. 15.2 Five-Membered Heterocycles Fused to Six-Membered Rings. 15.3 Two Fused Six-Membered Rings. 15.4 Heterodiazepines. 15.5 Heterocyclic Compounds with Three or More Rings. References. Subject Index. Reaction Index. Cross Index of Biological Activities.

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Book SynopsisKinase Inhibitor Drugs covers a wide and comprehensive range of topics about kinase-targeted inhibitors in cancer therapy, one of the hottest drug targets in modern drug discovery.Trade Review"In conclusion, I strongly recommend this book to anyone who is interested and new to the field of kinase inhibitors. Indeed, I believe this book should not merely sit on the shelves of kinase experts, but should be used frequently for reference." (ChemMedChem, 2010) "Delivers what the title promises: a comprehensive treatment of drugs that inhibit kinases. ... Will be interesting to any chemist or biologist desiring a behind-the-scenes look at modern strategies of drug discovery and their practical applications to some challenging targets." (Journal of Medicinal Chemistry, April 2010)Table of ContentsPREFACE. CONTRIBUTORS. PART I GROWTH FACTOR INHIBITORS: VEGFR2, ERBB2, AND OTHER KINASE. 1 Discovery and Development of Sunitinib (SU11248): A Multitarget Tyrosine Kinase Inhibitor of Tumor Growth, Survival, and Angiogenesis (Connie L. Sun, James G. Christensen, and Gerald McMahon). 2 Tykerb Discovery: A Dual EGFR and ERBB2 Tyrosine Kinase Inhibitor (Karen Lackey and G. Stuart Cockerill). 3 Discovery of Pazopanib: A Pan Vascular Endothelial Growth Factor Kinase Inhibitor (Philip A. Harris and Jeffrey A. Stafford). 4 Road to ABT-869: A Multitargeted Receptor Tyrosine Kinase Inhibitor (Michael Michaelides and Daniel H. Albert). 5 Discovery of Motesanib (Andrew S. Tasker and Vinod F. Patel). 6 Discovery of Brivanib Alaninate: A Dual Vascular Endothelial Growth Factor and Fibroblast Growth Factor Receptor Inhibitor (Rajeev S. Bhide and Joseph Fargnoli). 7 S tructure-Based Design and Characterization of Axitinib (Robert S. Kania). PART II GROWTH FACTOR INHIBITORS: MEK INHIBITORS. 8 Road to PD0325901 and Beyond: The MEK Inhibitor Quest (Judith S. Sebolt-Leopold and Alexander J. Bridges). 9 Discovery of Allosteric MEK Inhibitors (Eli Wallace and James F. Blake). PART III CELL CYCLE KINASE INHIBITORS: AURORA KINASE AND PLK INHIBITORS. 10 Discovery of MK-0457 (VX-680) (Julian M. C. Golec). 11 Discovery of PHA-739358 (Daniele Fancelli and Jürgen Moll). 12 Discovery of AZD1152: A Selective Inhibitor of Aurora-B Kinase with Potent Antitumor Activity (Kevin M. Foote and Andrew A. Mortlock). 13 Case Study of Aurora-A Inhibitor MLN8054 (Christopher F. Claiborne and Mark G. Manfredi). 14 Discovery of GSK461364: A Polo-like Kinase 1 Inhibitor for the Treatment of Cancer (Kevin W. Kuntz and Kyle A. Emmitte). PART IV RELATED SPECIAL TOPICS. 15 Pharmacogenomics of Dasatinib (Sprycel) (Fei Huang and Edwin A. Clark). 16 Practical Use of Computational Chemistry in Kinase Drug Discovery (James M. Veal). 17 Approaches to Kinase Homology Modeling: Successes and Considerations for the Structural Kinome (Victoria A. Feher and J. David Lawson). 18 Fragment-Based Drug Discovery of Kinase Inhibitors (Daniel A. Erlanson). 19 Protein Kinase Structural Biology: Methods and Strategies for Targeted Drug Discovery (Clifford D. Mol, Kengo Okada, and David J. Hosfield). INDEX.

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Book SynopsisThis book specifically addresses the safety aspects of compatibility for drugs and their delivery devices and containers. The author deals with issues such as how the leachables impact safety of a therapeutic product and, more importantly, how one ascertains the magnitude of the impact.Trade Review"The book provides a very detailed review of approaches for generating and further investigating extractables and leachables results, with advice on the levels of investigation appropriate to each stage of product development." (BTS Newsletter, Summer 2010) Table of ContentsPreface and Acknowledgments xv Part A General Concepts 1 1. Introduction 3 General Discussion 3 Key Definitions 6 The Interacting Parties 6 Extractables versus Leachables 7 Regulatory Perspectives for Performing Compatibility and/or Safety Assessments 13 The U.S. Food and Drug Administration Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics 14 European Medicines Agency (EMEA) Guideline on Plastic Immediate Packaging Materials 15 FDA Guidance for Industry Inhalation Products 18 Medical Devices 20 An Overview of Strategies for Performing Safety Assessments 21 The Generalized Strategy for Safety Assessments 22 Moving Forward 24 References 25 2. Nomenclature and General Concepts 27 General 27 Nomenclature 27 Primary Definitions 28 Constituents of a Material or Construct 29 Classification of Extracting Media 31 Classification of Extraction Strategies 32 Example Extraction Conditions Applied to a Model System 39 Correlation 43 Factors That Influence the Linking of Extractables and Leachables 44 A Hierarchy for Linkages between Extractables and Leachables 44 Decisions Concerning the Required Rigor for Linkages 47 Circumstances Requiring the Linking of Extractables and Leachables 48 Identification and Quantitation 50 Risks and Risk Management 55 Risk Categories Related to Biological Assessment of Medical Devices 58 Risk Categories Related to Assessment of Primary Packaging and/or Container–Closure Systems 58 The General Dimensions of Risk 64 Utilization of Risk Classification Profiles 68 Risk Classification in Indirect Contact Situations 71 The Construct Itself as a Contributor to Risk 73 References 74 3. Extractables, Leachables, and the Product Life Cycle 77 General 77 Discussion of the Components of the Master Flow Diagram 78 Observations 83 Application of the Process Map 87 Part B Material Characterization 89 4. Material Screening and Characterization 91 Overview 91 General Principles 94 Compendial Compliance 97 United States Pharmacopeia 98 Japanese Pharmaceopeia 101 European Pharmacopeia 102 Compositional Characterization, General Concepts 103 Compositional Characterization by Collecting Available Material Information 104 General 104 Collecting Extractables Information from the Material Supplier 106 Compositional Characterization by Material Testing, Extractables Survey 112 Extractables Survey: Extraction 112 Case Studies: The Influence of Extraction Medium on the Extractables Survey 121 Extractables Survey: Extract Analysis 124 Case Study: Extractables Survey for Plastic Tubing Materials 131 Case Study: Extractables Survey for an Elastomer Used in OINDP 136 Case Study: Extractables Survey for a Rubber Closure Used with Semisolid Drug Products 137 Case Study: Extractables Survey for Filter Cartridges Used in Downstream Processing of Pharmaceuticals 138 Bibliography of Analytical Methods 139 Reconciliation as a Survey Tool 140 Case Study: TOC Reconciliation; Characterization of a Polyolefin Material 141 Use of Extractables Information in Safety Assessment: Extractables Profile, Total Pool, and Total Available Pool 142 Extractions to Establish the Total Pool and Total Available Pool 143 Case Study: Total Pool Determination by Successive Extraction 145 Recap: Components of a Complete Extractables Assessment 146 Caveats in Using Extractables Information for Safety Assessment 149 Chemical Characterization: Device Perspective per ISO 10993-18 152 References 154 Part C Construct Qualification 157 5. The Prototype Stage 159 General Comments 159 The Simulation Study 161 Generating the Simulating Extract 162 Simulating the Contact Parameters 164 Simulating the Therapeutic Product 166 Simulating the Exposure Parameters 169 Analyzing the Simulating Extract 171 Case Study: Modeling of the Impact of Solubilizing Agents on Leachables Accumulation 172 Case Study: Accumulation of Organic Leachables from Plastic Biopharmaceutical Process Containers 174 Case Study: Accumulation of Label-Related Leachables in a Solid Dosage Form 179 Case Study: Accumulation of Caprolactam Oligomers Leached from Nylon-6 Material 180 Application of the Analytical Threshold 181 The Preliminary Toxicological Assessment 184 Case Study: Assessment of Cyclohexanone Limits for Containers 188 Exiting the Prototype Stage 188 References 189 6. The Early Development Stage 191 General Comments 191 Target Leachables 192 Method Development, Evaluation, and Validation 194 Method Development (Optimization) 195 Prerequisites to Method Optimization 195 Overview of the Method Optimization Process 197 Conduct of a Method Optimization Study 200 Primary Performance Assessment 201 Troubleshooting Guide 202 Secondary Performance Assessment 204 System Suitability 205 Robustness 205 Exiting Method Development–Optimization 206 The Method Evaluation Process 206 General 206 Aspects of the Evaluation and Validation Processes 207 Overview of the Method Evaluation Process 207 Template for the Conduct of a Method Evaluation Study 209 Validation 214 Case Study: Validation of an LC/MS Method for the Quantitation of Leachables from a Packaging System 215 General 215 Experimental 216 Validation Study 218 Case Study: Validation of an HPLC Method for Quantitating Stopper Leachables in a Complex Surfactant Vehicle 225 General 225 Validation 225 Exiting the Early Development Stage 228 References 228 Part D Construct Validation 229 7. Late Stage Product Development 231 General: The Migration Study 231 Design of the Migration Study 233 EMEA Guideline on Plastic Immediate Packaging Materials 233 FDA Guidance 233 Optimal Design of a Migration Study 234 Interpretation of the Migration Study: Toxicological Assessment 238 Disaster Management 238 Class A Disaster: Unusual or Unexpected Change in the Concentration of a Target Leachable 239 Class B Disaster: A Previously Unobserved Response is Obtained During Testing 241 Documenting a Disaster Investigation 242 Specificity Check in Drug Product Analysis Methods 242 Product Stability Issues Associated with Leachables 244 References 245 8. Submission 249 General Discussion 249 Dossier Format: The Common Technical Document 250 Contents of the CTD Sections Relevant to Container Closure Systems and Their Safety Assessment 252 Section 3.2.P.7, Description 252 Section 3.2.P.2.4, Suitability 254 Closing Observations 262 References 263 9. Launch 265 Part E Product Maintenance 271 10. Product Maintenance 273 General Discussion 273 Ongoing Quality Control 275 General 275 Incoming Raw Materials 275 Manufactured In-Process Goods 278 Finished Goods (Final Product) 279 Process of Developing–Implementing QC Extractables Specifications 281 Change Control 282 General 282 Change Control Impact Assessment 285 Evaluation Recommendation 295 Factors to Consider When Contemplating Changes to Registered Products 296 Case Study: Differential Approach 297 Overview 297 General Test Strategy 297 Experimental 298 Results and Discussion 299 Principles for Judging Toxicological Equivalency 304 Disaster Management During Product Maintenance 305 Atypical Manufacturing During Product Maintenance 305 Product Use Field Issues Encountered During Product Maintenance 309 Changes in Product Registration Requirements During Product Maintenance 312 Exiting the Product Maintenance Stage 313 References 313 11. Retirement 315 12. Focus on Emerging Concepts 319 Overview 319 Plastic Materials used in Manufacturing Applications 320 General 320 Regulatory Requirements 321 Industry Recommendations 322 Case Study: Leachables Evaluation for Bulk Drug Substance 326 Process for Performing Extractables and Leachables Assessments for Disposable Materials Used in Bioprocessing 327 A Matter of Semantics 328 Best Demonstrated Practices in Extractables Assessments 331 The Broader Context of Suitability for Use 337 An Important Practical Consideration 340 Future Considerations 342 References 344 Appendix: Materials Used in Pharmaceutical Constructs and Their Associated Extractables 347 References 370 Index 371

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Book SynopsisG protein-coupled receptors (GPCRs) are a large protein family of transmembrane receptors vital in dictating cellular responses. GPCRs are involved in many diseases, but are also the target of around half of all modern medicinal drugs. Shifting Paradigms in G Protein Coupled Receptors takes a look at the way GPCRs are examined today, how they react, how their mutations lead to disease, and the many ways in which they can be screened for compounds that modulate them. Chemists, pharmacologists, and biologists will find essential information in this comprehensive reference.Trade Review"Additionally, the presentation of the fundamental concepts of GPCR biology by the authors, who are recognized experts in the GPCR field, is likely to be appreciated by students of pharmacology. . . This is a unique resource for navigating the field of GPCR research." (Doody's, 23 September 2011) ". . . scientists whose area of research is (or will be) connected with GPCRs ... will get a comprehensive overview of current state-of-the-art research in this broad and rapidly developing field." (ChemMedChem, 1 February 2011)Table of ContentsPreface. Contributors. 1. The Evolution of Receptors: From On–Off Switches to Microprocessors (Terry Kenakin). 1.1. Introduction. 1.2. The Receptor as an On–Off Switch. 1.3. Historical Background and Classical Receptor Theory. 1.4. The Operational Model of Drug Action. 1.5. Receptor Antagonism. 1.6. Specific Models of GPCRs (7TM Receptors). 1.7. The Receptor as Microprocessor: Ternary Complex Models. 1.8. Receptors as Basic Drug Recognition Units. 1.9. Receptor Structure. 1.10. Future Considerations. References. 2. The Evolving Pharmacology of GPCRs 27 (Lauren T. May, Nicholas D. Holliday, and Stephen J. Hill). 2.1. Agonists, Neutral Antagonists, and Inverse Agonists. 2.2. LDTRS/Protean Agonism. 2.3. Molecular Mechanisms of GPCR Ligand Binding. 2.4. Two GPCR Ligands Binding at Once—Concept of Allosterism. 2.5. GPCR Dimerization. 2.6. Future Perspectives. Acknowledgments. References. 3. The Emergence of Allosteric Modulators for G Protein-Coupled Receptors (Karen J. Gregory, Celine Valant, John Simms, Patrick M. Sexton, and Arthur Christopoulos). 3.1. Introduction. 3.2. Foundations of Allosteric Receptor Theory. 3.3. Models for Understanding the Effects of Allosteric Modulators. 3.4. Types of Allosteric Modulators and Their Properties. 3.5. Detection and Quantification of Allosteric Interactions. 3.6. Some Examples of GPCR Allosteric Modulators. 3.7. Concluding Remarks. References. 4. Receptor-Mediated G Protein Activation: How, How Many, and Where? (Ingrid Gsandtner, Christian W. Gruber, and Michael Freissmuth). 4.1. The Mechanical Problem—Three Different Solutions. 4.2. Receptor Monomers–Dimers–Oligomers: One Size Fits All? 4.3. Corrals, Fences, Rafts—Are There Privileged Places for GPCR Activation? Acknowledgments. References. 5. Molecular Pharmacology of Frizzleds—with Implications for Possible Therapy (Gunnar Schulte). 5.1. Introduction. 5.2. Frizzleds as WNT Receptors. 5.3. Frizzled Signaling 120. 5.4. Frizzleds—Physiology and Possible Therapy. Acknowledgments. References. 6. Secretin Receptor Dimerization: A Possible Functionally Important Paradigm for Family B G Protein-Coupled Receptors (Kaleeckal G. Harikumar, Maoqing Dong, and Laurence J. Miller). 6.1. Methodological Approaches to GPCR Oligomerization. 6.2. Structural Themes for GPCR Oligomerization. 6.3. Functional Effects of GPCR Oligomerization. 6.4. Secretin Receptor Oligomerization. References. 7. Past and Future Strategies for GPCR Deorphanization (Angélique Levoye, Nathalie Clement, Elodie Tenconi and Ralf Jockers). 7.1. Introduction. 7.2. Current Strategies to Identify the Ligand and Function of Orphan 7TM Proteins. 7.3. Functional Assays for Deorphanization. 7.4. Future Directions and New Concepts. 7.5. Controversial Issues. Acknowledgments. References. 8. High-Throughput GPCR Screening Technologies and the Emerging Importance of the Cell Phenotype (Terry Reisine and Richard M. Eglen). 8.1. Introduction. 8.2. How Are GPCR Drugs Discovered? 8.3. GPCR Dependence on G Proteins. 8.4. Technologies for GPCR Compound Screening and Drug Discovery. 8.5. Importance of Target Cells in GPCR HTS Assays. 8.6. Summary. References. 9. Are "Traditional" Biochemical Techniques Out of Fashion in the New Era of GPCR Pharmacology? (Maria Teresa Dell’anno and Maria Rosa Mazzoni). 9.1. Overview. 9.2. Receptor Binding Assays. 9.3. Methods for Measurement of cAMP. 9.4. Conclusions. References. 10. Fluorescence and Resonance Energy Transfer Shine New Light on GPCR Function (Carsten Hoffmann and Moritz Bünemann). 10.1. Overview. 10.2. Introduction. 10.3. Labeling GPCRs with Fluorescent Tags. 10.4. Detection of Fluorescence and Bioluminescence. 10.5. Fluorescence-Based Assays to Study Receptor Localization, Trafficking and Receptor Function. 10.6. Resonance Energy Transfer, a Tool to Get New Insights into GPCR Function. 10.7. Analysis of Steady-State Protein–Protein Interaction by Means of RET. 10.8. Kinetic Analysis of Protein–Protein Interactions by Means of FRET. 10.9. Detection of Receptor Function by Fluorescence Resonance Energy. References. 11. Integration of Label-Free Detection Methods in GPCR Drug Discovery (Oliver Nayler, Magdalena Birker-Robaczewska, and John Gatfield). 11.1. Overview. 11.2. Introduction. 11.3. Label-Free Technologies—Past and Present. 11.4. Discussion. Acknowledgments. References. 12. Screening for Allosteric Modulators of G Protein-Coupled Receptors (Christopher Langmead). 12.1. Introduction. 12.2. The Allosteric Ternary Complex Model, Radioligand Binding, and Affinity. 12.3. Beyond Affinity—Functional Assays, Efficacy, and Allosteric Agonism. 12.4. Allosteric Modulator Titration Curves. 12.5. The Impact of Functional Assay Format on Allosteric Modulator Screening. 12.6. Taking Advantage of Structural Understanding of Allosteric Binding Sites. 12.7. Summary and Future Directions. References. 13. Ultra-High-Throughput Screening Assays for GPCRs (Priya Kunapuli). 13.1. Introduction. 13.2. Assay Types for GPCRs in uHTS. 13.3. Summary. Acknowledgments. References. 14. New Techniques to Express and Crystallize G Protein-Coupled Receptors (James C. Errey and Fiona H. Marshall). 14.1. Introduction. 14.2. Key Problems Limiting Production of 3D GPCR Structures. 14.3. History of GPCR Structures. 14.4. The Search for Other GPCR Structures. 14.5. Protein Purification and Solubilization. 14.6. In Cubo Crystallization. 14.7. Engineering Receptor Stability. 14.8. Structures of the â2AR. 14.9. The Adenosine A2a Receptor. 14.10. Conclusions and Future Developments. Acknowledgments. References. 15. Structure and Modeling of GPCRs: Implications for Drug Discovery (Kimberly A. Reynolds, Vsevolod Katritch, and Ruben Abagyan). 15.1. Introduction. 15.2. High-Resolution GPCR Modeling. 15.3. Constructing and Evaluating Homology Models of Other Receptor Types. 15.4. Modeling GPCR Functional Features—Analysis of Activation and Signaling. 15.5. Beyond Class A: Modeling of Other GPCR Families. 15.6. Summary and Conclusions. Acknowledgments. References. 16. X-Ray Structure Developments for GPCR Drug Targets (Michael Sabio and Sidney W. Topiol). 16.1. Overview. 16.2. Introduction. 16.3. Class A GPCRs. 16.4. Class C GPCRs. 16.5. Conclusions. References. 17. Pharmacological Chaperones: Potential for the Treatment of Hereditary Diseases Caused by Mutations in G Protein-Coupled Receptors (Kenneth J. Valenzano, Elfrida R. Benjamin,Patricia René, and Michel Bouvier). 17.1. Overview. 17.2. Introduction. 17.3. NDI and the V2R. 17.4. RP and the Rhodopsin Receptor. 17.5. IHH and the Gonadotropin-Releasing Hormone Receptor. 17.6. Other Human Diseases Caused by Inactivating Mutations in GPCRs. 17.7. Considerations for the Therapeutic Use of Pharmacological Chaperones. 17.8. Concluding Remarks. Acknowledgments. References. Index.

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Book SynopsisThe definitive book on the neutralization of recombinant biopharmaceuticals Recombinant biopharmaceuticals are an important tool for treating a range of illnesses; however, their efficacy can be severely impaired by their immunogenicity. When introduced into the body, these pharmaceuticals can cause the immune system to produce anti-drug antibodies (ADAs) that neutralize their effects. The first and only book to cover neutralization in connection with biopharmaceuticals and the measurement and application of neutralizing antibodies in modern medicine at any real length, Detection and Quantification of Antibodies to Biopharmaceuticals: Practical and Applied Considerations offers a comprehensive and in-depth look at all the principal aspects of the detection and quantification of antibodies that are essential to understanding and responding to the challenges they present. Bringing together a large-scale review of neutralization and biopharmaceuticals and the abiliTable of ContentsINTRODUCTION: A PERSPECTIVE ix Michael G. Tovey CONTRIBUTORS xxi PART I RISK-BASED STRATEGIES 1 1 Principles of Risk Assessment and Monitoring of Antibody Responses to Biopharmaceuticals 3 Eugen Koren, Erik Foehr, and Charles A. O’Neill PART II REGULATORY REQUIREMENTS 13 2 Immunogenicity of Therapeutic Proteins: A Regulatory Perspective 15 Susan Kirshner 3 Guidance on Immunogenicity Assessment of Biologically Derived Therapeutic Proteins: A European Perspective 37 Meenu Wadhwa and Robin Thorpe 4 Japanese Regulatory Perspective on Immunogenicity 57 Takao Hayakawa and Akiko Ishii-Watabe PART III PRINCIPAL TECHNOLOGIES EMPLOYED FOR THE QUANTIFICATION OF ANTI-DRUG ANTIBODIES 81 5 Enzyme Immunoassays and Radioimmunoassays for Quantification of Anti-TNF Biopharmaceuticals and Anti-Drug Antibodies 83 Klaus Bendtzen and Morten Svenson 6 Confirmatory Immunogenicity Assays 103 Eric Wakshull and Daniel Coleman 7 The Use of Pharmacodynamics as a Surrogate Marker for the Detection of Anti-Drug Neutralizing Antibodies 119 Florian Deisenhammer 8 Cell-Based Assays for the Detection of Neutralizing Antibodies to Interferon Beta (IFN-β) and Tumor Necrosis Factor Alpha (TNF-α) Inhibitors 133 Anthony Meager 9 Detection of Neutralizing Antibodies against Interferon Beta by Real-Time RT-PCR 157 Francesca Gilli and Antonio Bertolotto 10 Competitive Ligand-Binding Assays for the Detection of Neutralizing Antibodies 175 Bonnie W. Wu, George R. Gunn III, and Gopi Shankar 11 The Use of Surface Plasmon Resonance for the Detection and Characterization of Antibodies 193 Steven J. Swanson and Daniel Mytych 12 Hypersensitivity Reactions to Biopharmaceuticals: Detection and Quantification of Drug-Specific IgE Antibodies 211 Jörgen Dahlström and Lennart Venemalm PART IV ASSAY STANDARDIZATION AND VALIDATION 233 13 Standardization and Validation of Immunoassays 235 Daniel Kramer 14 Standardization and Validation of Cell-Based Assays for the Detection of Neutralizing Anti-Drug Antibodies 243 Deborah Finco-Kent and Amy Grenham 15 Standardization of Neutralizing Antibody Unitage by Bioassay Design: Constant Antigen and Constant Antibody Methodology 269 Sidney E. Grossberg, Yoshimi Kawade, and Leslie D. Grossberg PART V STATISTICAL CONSIDERATIONS 287 16 Cut Points and Performance Characteristics for Anti-Drug Antibody Assays 289 Viswanath Devanarayan and Michael G. Tovey 17 Dilutional Linearity for Neutralizing Antibody Assays 309 David Lansky and Carrie Wager PART VI ADAPTATION OF ANTI-DRUG ANTIBODY ASSAYS TO CHALLENGING CONDITIONS 319 18 Detection of Antibodies to Biopharmaceuticals in the Presence of High Levels of Circulating Drug 321 Arno Kromminga and Michael G. Tovey 19 Antibody Assays in Animal Research 331 Vera Brinks, Francesca Gilli, Melody Sauerborn, and Huub Schellekens 20 Immunogenicity of Microbial Digestive Enzymes for Oral Replacement Therapy in Pancreatic Exocrine Insufficiency 343 Claudia Berger and Uwe Niesner PART VII NOVEL TECHNOLOGIES FOR THE QUANTIFICATION OF NEUTRALIZING ANTIBODIES 369 21 Measurement of Biologically Active Drug as an Approach to Detection of Anti-Drug Neutralizing Antibodies 371 Yao Zhuang and Shalini Gupta 22 A Novel One-Step Cell-Based Assay for Quantification of Neutralizing Antibodies to Biopharmaceuticals 383 Christophe Lallemand and Michael G. Tovey INDEX 399

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Book SynopsisUsing case studies of successful drug discoveries and launches, this book helps master the necessary knowledge of the drug discovery process. It includes pharmacology, drug metabolism, biology, drug development, and clinical studies.Trade Review“This book will enrich the collection of medicinal chemists or pharmacologists involved in active drug discovery research, as well as students with a passion for pursuing a career in drug discovery.” (Doody’s, 22 February 2013) "A well-made glossary is available in the appendix, which defines the dozens of terms that a medicinal chemist will encounter in his/her career. . . This book demonstrates yet again the need for new, better medicines and the reasons for the high cost of drug research. An enjoyable read!.” (ChemMedChem, 1 January 2013)Table of ContentsPreface xv Contributors xvii Chapter 1 Introduction: Drug Discovery in Difficult Times 1Malcolm MacCoss Chapter 2 Discovery and Development of The DPP-4 Inhibitor Januvia® (SITA-GLIPTIN) 10Emma R. Parmee, Ranabir SinhaRoy, Feng Xu, Jeffrey C. Givand, and Lawrence A. Rosen 2.1 Introduction 10 2.2 DPP-4 Inhibition as a Therapy for Type 2 Diabetes: Identification of Key Determinants for Efficacy and Safety 10 2.2.1 Incretin-Based Therapy for T2DM 10 2.2.2 Biological Rationale: DPP-4 is a Key Regulator of Incretin Activity 11 2.2.3 Injectable GLP-1 Mimetics for the Treatment of T2DM 12 2.2.4 DPP-4 Inhibition as Oral Incretin-Based Therapy for T2DM 12 2.2.5 Investigation of DPP-4 Biology: Identification of Candidate Substrates 13 2.2.6 Preclinical Toxicities of In-Licensed DPP-4 Inhibitors 15 2.2.7 Correlation of Preclinical Toxicity with Off-Target Inhibition of Pro-Specific Dipeptidase Activity 16 2.2.8 Identification of Pro-Specific Dipeptidases Differentially Inhibited by the Probiodrug Compounds 17 2.2.9 A Highly Selective DPP-4 Inhibitor is Safe and Well Tolerated in Preclinical Species 19 2.2.10 A Highly Selective DPP-4 Inhibitor Does Not Inhibit T-Cell Proliferation in vitro 19 2.2.11 DPP-4 Inhibitor Selectivity as a Key Parameter for Drug Development 20 2.3 Medicinal Chemistry Program 20 2.3.1 Lead Generation Approaches 20 2.3.2 Cyclohexyl Glycine α-Amino Acid Series of DPP-4 Inhibitors 20 2.3.3 Improving Selectivity of theα-Amino Acid Series 22 2.3.4 Identification and Optimization of the β-Amino Acid Series 22 2.4 Synthetic and Manufacturing Routes to Sitagliptin 27 2.4.1 Medicinal Chemistry Route to Sitagliptin and Early Modifications 27 2.4.2 An Asymmetric Hydrogenation Manufacturing Route to Sitagliptin 28 2.4.3 A “Greener” Manufacturing Route to Sitagliptin Employing Biocatalytic Transamination 31 2.5 Drug Product Development 33 2.5.1 Overview 33 2.5.2 Composition Development 33 2.5.3 Manufacturing Process Development 33 2.6 Clinical Studies 36 2.6.1 Preclinical PD Studies and Early Clinical Development of Sitagliptin 36 2.6.2 Summary of Phase II/III Clinical Trials 38 2.7 Summary 39 References 39 Chapter 3 Olmesartan Medoxomil: An Angiotensin II Receptor Blocker 45Hiroaki Yanagisawa, Hiroyuki Koike, and Shin-ichiro Miura 3.1 Background 45 3.1.1 Introduction 45 3.1.2 Prototype of Orally Active ARBs 46 3.2 The Discovery of Olmesartan Medoxomil (Benicar) 47 3.2.1 Lead Generation 47 3.2.2 Lead Optimization 49 3.3 Characteristics of Olmesartan 53 3.4 Binding Sites of Omlersartan to the AT1 Receptor and Its Inverse Agonoist Activity 56 3.4.1 Binding Sites of Olmesartan to the AT1 Receptor 56 3.4.2 Inverse Agonist Activity of Olmesartan 56 3.4.3 Molecular Model of the Interaction between Olmesartan and the AT1 Receptor 57 3.5 Practical Preparation of Olmesartan Medoxomil 58 3.6 Preclinical Studies 58 3.6.1 AT1 Receptor Blocking Action 58 3.6.2 Inhibition of Ang II-Induced Vascular Contraction 59 3.6.3 Inhibition of the Pressor Response to Ang II 60 3.6.4 Blood Pressure Lowering Effects 60 3.6.5 Organ Protection 61 3.7 Clinical Studies 62 3.7.1 Antihypertensive Efficacy and Safety 62 3.7.2 Organ Protection 63 3.8 Conclusion 63 References 64 Chapter 4 Discovery of Heterocyclic Phosphonic Acids as Novelampmimics That Are Potent and Selective Fructose-1,6-Bisphosphatase Inhibitors and Elicit Potent Glucose-Lowering Effects in Diabetic Animals and Humans 67Qun Dang and Mark D. Erion 4.1 Introduction 67 4.2 The Discovery of MB06322 69 4.2.1 Research Operation Plan 69 4.2.2 Discovery of Nonnucleotide AMP Mimics as FBPase Inhibitors 69 4.2.3 Discovery of Benzimidazole Phosphonic Acids as FBPase Inhibitors 74 4.2.4 Discovery of Thiazole Phosphonic Acids as Potent and Selective FBPase Inhibitors 77 4.2.5 The Discovery of MB06322 Through Prodrug Strategy 80 4.3 Pharmacokinetic Studies of MB06322 82 4.4 Synthetic Routes to MB06322 83 4.5 Clinical Studies of MB06322 83 4.5.1 Efficacy Study of Thiazole 12.6 in Rodent Models of T2DM 83 4.5.2 Phase I/II Clinical Studies 84 4.6 Summary 84 References 85 Chapter 5 Setting The Paradigm of Targeted Drugs for The Treatment of Cancer: Imatinib and Nilotinib, Therapies for Chronic Myelogenous Leukemia 88Paul W. Manley and Jurg Zimmermann 5.1 Introduction 88 5.2 Chronic Myelogenous Leukemia (CML) and Early Treatment of the Disease 89 5.3 Imatinib: A Treatment for Chronic Myelogenous Leukemia (CML) 92 5.4 The Need for New Inhibitorts of BCR-ABL1 and Development of Nilotinib 94 5.5 Conclusion 99 References 100 Chapter 6 Amrubicin, A Completely Synthetic 9-Aminoanthracycline for Extensive-Disease Small-Cell Lung Cancer 103Mitsuharu Hanada 6.1 Introduction 103 6.2 The Discovery of Amrubicin: The First Completely Synthetic Anthracycline 106 6.3 Toxicological Profile of Amrubicin 107 6.4 DNA Topoisomerase II Inhibition and Apoptosis Induction by Amrubicin 110 6.5 Amrubicin Metabolism: The Discovery of Amrubicinol 113 6.5.1 Amrubicinol Functions as an Active Metabolite of Amrubicin 113 6.5.2 Tumor-Selective Metabolism of Amrubicin to Amrubicinol 115 6.6 Improved Usage of Amrubicin 116 6.7 Clinical Trials 118 6.7.1 Clinical Trials of Amrubicin as First-line Therapy in Patients with ED-SCLC 118 6.7.2 Clinical Trials of Amrubicin as Second-Line Therapy in Patients with ED-SCLC 121 6.8 Conclusions 122 References 123 Chapter 7 The Discovery of Dual IGF-1R and IR Inhibitor FQIT for the Treatment of Cancer 127Meizhong Jin, Elizabeth Buck, and Mark J. Mulvihill 7.1 Biological Rational for Targeting the IGF-1R/IR Pathway for Anti-Cancer Therapy 127 7.2 Discovery of OSI-906 128 7.2.1 Summary of OSI-906 Discovery 128 7.2.2 OSI-906 Clinical Aspects 129 7.3 OSI-906 Back Up Efforts 131 7.4 The Discovery of FQIT 131 7.4.1 Lead Generation Strategy 131 7.4.2 Small Molecule Dual IGF-1R/IR Inhibitor Drug Discovery Cascade 133 7.4.3 Initial Proof-of-Concept Compounds 134 7.4.4 Synthesis of 5,7-Disubstituted Imidazo[5,1-f][1,2,4] Triazines 135 7.4.5 Lead Imidazo[5,1-f][1,2,4] Triazine IGF-1R/IR Inhibitors and Emergence of FQIT 139 7.5 In Vitro Profile of FQIT 140 7.5.1 Cellular and Antiproliferative Effects as a Result of IGF-1R and IR Inhibition 140 7.5.2 Cellular Potency in the Presence of Plasma Proteins 141 7.5.3 In Vitro Metabolism and CYP450 Profile 143 7.6 Pharmacokinetic Properties of FQIT 144 7.6.1 formulation and Salt Study 144 7.6.2 Pharmacokinetics Following Intravenous Administration 144 7.6.3 Pharmacokinetics Following Oral Administration 145 7.7 In Vivo Profile of FQIT 146 7.7.1 In Vivo Pharmacodynamic and PK/PD Correlation 146 7.7.2 In Vivo Efficacy 146 7.8 Safety Assessment and Selectivity Profile of FQIT 148 7.8.1 Effects on Blood Glucose and Insulin Levels 148 7.8.2 Oral Glucose Tolerance Test 148 7.8.3 Ames, Rodent, and Nonrodent Toxicology Studies 149 7.8.4 Selectivity Profile of FQIT 149 7.9 Summary 150 Acknowledgments 151 References 151 Chapter 8 Discovery and Development of Montelukast (Singulair®) 154Robert N. Young 8.1 Introduction 154 8.2 Drug Development Strategies 158 8.3 LTD4 Antagonist Program 159 8.3.1 Lead Generation and Optimization 159 8.3.2 In Vitro and In Vivo Assays 159 8.4 The Discovery of Montelukast (Singulair®) 160 8.4.1 First-Generation Antagonists (Figure 8.3) 160 8.4.2 Discovery of MK-571 163 8.4.3 Discovery of MK-0679 (29) 168 8.4.4 Discovery of Montelukast (L-706,631, MK-0476, Singulair®) 171 8.5 Synthesis of Montelukast 174 8.5.1 Medicinal Chemistry Synthesis 174 8.5.2 Process Chemistry Synthesis [104, 105] (Schemes 8.5 and 8.6) 176 8.6 ADME Studies with MK-0476 (Montelukast) 179 8.7 Safety Assessment of Montelukast 180 8.8 Clinical Development of Montelukast 180 8.8.1 Human Pharmacokinetics, Safety, and Tolerability 180 8.8.2 Human Pharmacology 181 8.8.3 Phase 2 Studies in Asthma 182 8.8.4 Phase 3 Studies in Asthma 182 8.8.5 Effects of Montelukast on Inflammation 185 8.8.6 Montelukast and Allergic Rhinitis 185 8.9 Summary 185 8.9.1 Impact on Society 185 8.9.2 Lessons Learned 186 8.10 Personal Impact 187 References 188 Chapter 9 Discovery and Development of Maraviroc, A CCR5 Antagonist for the Treatment of HIV Infection 196Patrick Dorr, Blanda Stammen, and Elna van der Ryst 9.1 Background and Rationale 196 9.2 The Discovery of Maraviroc 199 9.2.1 HTS and Biological Screening to Guide Medicinal Chemistry 199 9.2.2 Hit Optimization 200 9.2.3 Overcoming Binding to hERG 201 9.3 Preclinical Studies 201 9.3.1 Metabolism and Pharmacokinetic Characteristics of Maraviroc 201 9.3.2 Maraviroc Preclinical Pharmacology 202 9.3.3 Preclinical Investigations into HIV Resistance 202 9.3.4 Binding of Maraviroc to CCR5 204 9.4 The Synthesis of Maraviroc 205 9.5 Nonclinical Safety and Toxicity Studies 206 9.5.1 Safety Pharmacology 206 9.5.2 Immuno- and Mechanistic Toxicity 206 9.6 Clinical Development of Maraviroc 207 9.6.1 Phase 1 Studies 207 9.6.2 Phase 2a Studies 209 9.6.3 Phase 2b/3 Studies 210 9.6.4 Development of Resistance to CCR5 Antagonists In Vivo 213 9.7 Summary, Future Directions, and Challenges 214 Acknowledgments 217 References 217 Chapter 10 Discovery of Antimalarial Drug Artemisinin and Beyond 227Weiwei Mao, Yu Zhang, and Ao Zhang 10.1 Introduction: Natural Products in Drug Discovery 227 10.2 Natural Product Drug Discovery in China 227 10.3 Discovery of Artemisinin: Background, Structural Elucidation and Pharmacological Evaluation 228 10.3.1 Background and Biological Rationale 228 10.3.2 The Discovery of Artemisinin through Nontraditional Drug Discovery Process 229 10.3.3 Structural Determination of Artemisinin 231 10.3.4 Pharmacological Evaluation and Clinical Trial Summary of Artemisinin 231 10.4 The Synthesis of Artemisinin 232 10.4.1 Synthesis of Artemisinin using Photooxidation of Cyclic or Acyclic Enol Ether as the Key Step 233 10.4.2 Synthesis of Artemisinin by Photooxidation of Dihydroarteannuic Acid 236 10.4.3 Synthesis of Artemisinin by Ozonolysis of a Vinylsilane Intermediate 236 10.5 SAR Studies of Structural Derivatives of Artemisinin: The Discovery of Artemether 238 10.5.1 C-10-Derived Artemisinin Analogs 240 10.5.2 C-9 and C-9,10 Double Substituted Analogs 245 10.5.3 C-3 Substituted Analogs 246 10.5.4 C-6 or C-7 Substituted Derivatives 246 10.5.5 C-11-Substituted Analogs 247 10.6 Development of Artemether 248 10.6.1 Profile and Synthesis of Artemether 248 10.6.2 Clinical Studies Aspects of Artemether 249 10.7 Conclusion and Perspective 250 Acknowledgment 250 References 251 Chapter 11 Discovery and Process Development of MK-4965, A Potent Nonnucleoside Reverse Transcriptase Inhibitor 257Yong-Li Zhong, Thomas J. Tucker, and Jingjun Yin 11.1 Introduction 257 11.2 The Discovery of MK-4965 260 11.2.1 Background Information 260 11.2.2 SAR Studies Leading to the Discovery of MK-4965 262 11.3 Preclinical and Clinical Studies of MK-4965 (19) 266 11.4 Summary of Back-Up SAR Studies of MK-4965 Series 266 11.5 Process Development of MK-4965 (19) 267 11.5.1 Medicinal Chemistry Route 267 11.5.2 Process Development 269 11.6 Conclusion 290 11.6.1 Lessons Learned from the Medicinal Chemistry Effort of MK-4965 Discovery 290 11.6.2 Summary and Lessons Learned from the Process Development of MK-4965 291 Acknowledgments 291 References 291 Chapter 12 Discovery of Boceprevir and Narlaprevir: The First and Second Generation of HCV NS3 Protease Inhibitors 296Kevin X. Chen and F. George Njoroge 12.1 Introduction 296 12.2 HCV NS3 Protease Inhibitors 298 12.3 Research Operation Plan and Biological Assays 302 12.3.1 Research Operation Plan 302 12.3.2 Enzyme Assay 302 12.3.3 Replicon Assay 302 12.3.4 Measure of Selectivity 303 12.4 Discovery of Boceprevir 303 12.4.1 Initial Lead Generation Through Structure-Based Drug Design 303 12.4.2 SAR Studies Focusing on Truncation, Depeptization, and Macrocyclisation 304 12.4.3 Individual Amino Acid Residue Modifications 307 12.4.4 Correlations Between P1, P3, and P3 Capping: The Identification of Boceprevir 315 12.5 Profile of Boceprevir 317 12.5.1 In Vitro Characterization of Boceprevir 317 12.5.2 Pharmacokinetics of Boceprevir 317 12.5.3 The Interaction of Boceprevir with NS3 Protease 318 12.6 Clinical Development and Approval of Boceprevir 319 12.7 Synthesis of Boceprevir 319 12.8 Discovery of Narlaprevir 322 12.8.1 Criteria for the Back-up Program of Boceprevir 322 12.8.2 SAR Studies 322 12.8.3 Profile of Narlaprevir 326 12.8.4 Clinical Development Aspects of Narlaprevir 327 12.8.5 Synthesis of Narlaprevir 327 12.9 Summary 329 References 330 Chapter 13 The Discoveryofsamsca® (Tolvaptan): Thefirst Oral Nonpeptide Vasopressin Receptor Antagonist 336Kazumi Kondo and Yoshitaka Yamamura 13.1 Background Information about the Disease 336 13.2 Biological Rational 337 13.3 Lead Generation Strategies: The Discovery of Mozavaptan 338 13.4 Lead Optimization: From Mozavaptan to Tolvaptan 347 13.5 Pharmacological Profiles of Tolvaptan 350 13.5.1 Antagonistic Affinities of Tolvaptan for AVP Receptors 350 13.5.2 Aquaretic Effect Following a Single Dose in Conscious Rats 352 13.6 Drug Development 353 13.6.1 Synthetic Route of Discovery and Commercial Synthesis [10a] 353 13.6.2 Nonclinical Toxicology 353 13.6.3 Clinical Studies 355 13.7 Summary Focusing on Lessons Learned 356 Acknowledgments 357 References 357 Chapter 14 Silodosin (Urief®, Rapaflo®, Thrupas®, Urorec®, Silodix®): A Selective α1A Adrenoceptor Antagonist for the Treatment of Benign Prostatic Hyperplasia 360Masaki Yoshida, Imao Mikoshiba, Katsuyoshi Akiyama, and Junzo Kudoh 14.1 Background Information 360 14.1.1 Benign Prostatic Hyperplasia 360 14.1.2 α1-Adrenergic Receptors 361 14.2 The Discovery of Silodosin 362 14.2.1 Medicinal Chemistry 362 14.2.2 The Synthesis of Silodosin (Discovery Route) 363 14.2.3 Receptor Binding Studies 365 14.3 Pharmacology of Silodosin 369 14.3.1 Action Against Noradrenalin-Induced Contraction of Lower Urinary Tract Tissue 369 14.3.2 Actions Against Phenylephrine-Induced Increase in Intraurethral Pressure and Blood Pressure 371 14.3.3 Actions Against Intraurethral Pressure Increased by Stimulating Hypogastric Nerve and Blood Pressure in Dogs with Benign Prostatic Hyperplasia 372 14.3.4 Safety Pharmacology 373 14.4 Metabolism of Silodosin 373 14.5 Pharmacokinetics of Silodosin 376 14.5.1 Absorption 376 14.5.2 Organ Distribution 377 14.5.3 Excretion 378 14.6 Toxicology of Silodosin 379 14.7 Clinical Trials 382 14.7.1 Phase I Studies 382 14.7.2 Phase III Randomized, Placebo-Controlled, Double-Blind Study 383 14.7.3 Long-Term Administration Study 385 14.8 Summary: Key Lessons Learned 388 References 389 Chapter 15 Raloxifene: A Selective Estrogen Receptor Modulator (SERM) 392Jeffrey A. Dodge and Henry U. Bryant 15.1 Introduction: SERMs 392 15.2 The Benzothiophene Scaffold: A New Class of SERMs 394 15.3 Assays for Biological Evaluation of Tissue Selectivity 394 15.4 Benzothiophene Structure Activity 395 15.5 The Synthesis of Raloxifene 401 15.6 SERM Mechanism 402 15.7 Raloxifene Pharmacology 405 15.7.1 Skeletal System 405 15.7.2 Reproductive System—Uterus 407 15.7.3 Reproductive System—Mammary 408 15.7.4 General Safety Profile and Other Pharmacological Considerations 410 15.8 Summary 411 References 411 Appendix I Small Molecule Drug Discovery and Development Paradigm 417 Appendix II Glossary 419 Appendix III Abbreviations 432 Index 443

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Book SynopsisAn overview of the new technologies that have revolutionized organic chemistry and allowed easy access to complex bioactives, this book brings modern synthetic techniques and bioactives together. The synthesis of structurally complex molecules has become a real challenge for the synthetic community.Table of ContentsFOREWORD vii PREFACE ix CONTRIBUTORS xi CHAPTER 1 C–H FUNCTIONALIZATION: A NEW STRATEGY FOR THE SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS 1 Sophie Rousseaux, Benoýˆt Lie´gault, and Keith Fagnou CHAPTER 2 THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES 33 Evelina Colacino, Jean Martinez, and Fre´de´ric Lamaty CHAPTER 3 METAL-CATALYZED C–HETEROATOM CROSS-COUPLING REACTIONS 77 Renata Marcia de Figueiredo, Jean Marc Campagne, and Damien Prim CHAPTER 4 GOLDEN OPPORTUNITIES IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOLOGICALLY ACTIVE COMPOUNDS 111 Fabien Gagosz CHAPTER 5 METATHESIS-BASED SYNTHESIS OF COMPLEX BIOACTIVES 155 Jean-Alexandre Richard, Sin Yee Ng, and David Y.-K. Chen CHAPTER 6 ENANTIOSELECTIVE ORGANOCATALYSIS: A POWERFUL TOOL FOR THE SYNTHESIS OF BIOACTIVE MOLECULES 189 Mitsuru Shoji and Yujiro Hayashi CHAPTER 7 ASYMMETRIC PHASE-TRANSFER CATALYSIS 213 Seiji Shirakawa, Shin A. Moteki, and Keiji Maruoka CHAPTER 8 REARRANGEMENTS IN NATURAL PRODUCT SYNTHESIS 243 Jose´ Marco-Contelles and Elena Soriano CHAPTER 9 DOMINO REACTIONS IN THE ENANTIOSELECTIVE SYNTHESIS OF BIOACTIVE NATURAL PRODUCTS 271 Lutz F. Tietze, Scott G. Stewart, and Alexander Du¨fert CHAPTER 10 FLUOROUS LINKER-FACILITATED SYNTHESIS OF BIOLOGICALLY INTERESTING MOLECULES 335 Wei Zhang CHAPTER 11 THE EVOLUTION OF IMMOBILIZED REAGENTS AND THEIR APPLICATION IN FLOW CHEMISTRY FOR THE SYNTHESIS OF NATURAL PRODUCTS AND PHARMACEUTICAL COMPOUNDS 359 Rebecca M. Myers, Kimberley A. Roper, Ian R. Baxendale, and Steven V. Ley CHAPTER 12 SYNTHETIC APPROACHES TO BIOACTIVE CARBOHYDRATES 395 Xavier Guinchard, Se´bastien Picard, and David Crich CHAPTER 13 AMMONIUM YLIDES AS BUILDING BLOCKS FOR ALKALOID SYNTHESIS 433 Scott Bur and Albert Padwa CHAPTER 14 PRECURSOR-DIRECTED BIOSYNTHESIS OF POLYKETIDE AND NONRIBOSOMAL PEPTIDE NATURAL PRODUCTS 485 Colin J. B. Harvey and Chaitan Khosla CHAPTER 15 TARGET-ORIENTED AND DIVERSITY-ORIENTED ORGANIC SYNTHESIS 513 Raphae¨l Rodriguez CHAPTER 16 DNA AS A TOOL FOR MOLECULAR DISCOVERY 539 Michael Smietana, Jean-Jacques Vasseur, Janine Cossy, and Stellios Arseniyadis INDEX 557

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Book SynopsisCost-effective strategies for designing novel drug delivery systems that target a broad range of disease conditions In vivo imaging has become an important tool for the development of new drug delivery systems, shedding new light on the pharmacokinetics, biodistribution, bioavailability, local concentration, and clearance of drug substances for the treatment of human disease, most notably cancer. Written by a team of international experts, this book examines the use of quantitative imaging techniques in designing and evaluating novel drug delivery systems and applications. Drug Delivery Applications of Noninvasive Imaging offers a full arsenal of tested and proven methods, practices and guidance, enabling readers to overcome the many challenges in creating successful new drug delivery systems. The book begins with an introduction to molecular imaging. Next, it covers: In vivo imaging techniques and quantitative analysis Table of ContentsPreface ix contributors xi 1 Introduction to Molecular Imaging 1 Vikas Kundra 2 PET/SPECT: Instrumentation and Imaging Techniques 12 Yuan-Chuan Tai 3 Photoacoustic Tomography and Its Applications in Drug Delivery and Photothermal Therapy 45 Liang Song and Lihong V. Wang 4 Raman Microspectral Imaging for Label-Free Detection of Nanoparticle-Mediated Cellular and Subcellular Drug Delivery 70 Tatyana Chernenko, Lara Milane, Christian Matthäus, Max Diem, and Mansoor Amiji 5 A natomical and Functional MRI91 Edward F. Jackson 6 Quantitative Imaging in Drug Delivery 125 Kooresh I. Shoghi 7 PET Imaging of the Pharmacokinetics of Small Molecular-Weight Drugs 147 Stephen M. Moerlein and Zhude Tu 8 Imaging Peptides, Proteins, and Antibody Delivery 192 Frederik L. Giesel and Clemens Kratochwil 9 In Vivo Imaging and Delivery of siRNA199 Zdravka Medarova and Anna Moore 10 Imaging Cell Therapy 223 Yajie Liang and Jeff W. M. Bulte 11 Radiolabeled Liposomes as Drug Delivery Nanotheranostics 252 William T. Phillips, Ande Bao, Keitaro Sou, Shihong Li, and Beth Goins 12 Polymeric Micelles as Imaging Agents and Drug Delivery Systems 268 Jun Zhao and Chun Li 13 Perfluorocarbon Nanoparticles: Translating Bench Opportunities to the Clinic 296 G. M. Lanza, P. M. Winter, S. D. Caruthers, A. H. Schmieder, and S. A. Wickline 14 Cancer Theranostics with Hollow Gold Nanospheres 308 Wei Lu and Chun Li 15 Imaging Pulmonary Drug Delivery 333 Stephen P. Newman 16 In Vivo Imaging for Validation of Oral Dose Performance 367 Fiona J. McInnes and Howard N. E. Stevens 17 Role of Large Animal Models in Translational Studies of Imaging and Targeted Drug Delivery 389 Rajesh K. Uthamanthil and Mei Tian 18 Imaging Transcatheter Delivery to Liver Tumors 412 Adil Al-Nahhas, Meeran Naji, and Imene Zerizer 19 Direct Visualization of Therapeutic Radionuclide Distribution Using Nuclear Medicine Imaging: I-131 in Metastatic Thyroid Carcinoma 426 Ho Young Lee, June-Key Chung, So Won Oh, Jong Jin Lee, Keon Wook Kang, Do Joon Park, Bo Youn Cho, and Myung Chul Lee 20 Imaging Drug Delivery to the CNS Using Translational Positron Emission Tomography Studies 432 Chi-Ming Lee, Katarina Varnäs, and Lars Farde Index 449

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Book Synopsis* Hemovigilance is a quality process which aims to improve quality and increase safety of blood transfusion, by surveying all activities of the blood transfusion chain, from donors to recipients. Hemovigilance programmes have now been in existence for over 15 years, but many countries and centers are still at the development stage. This valuable resource brings together the main elements of such programmes and shows the different types of models available. A general introduction includes Chapters on hemovigilance as a quality tool for transfusion as well as concepts of and models for hemovigilance. The core of the book describes how Hemovigilance systems have been set up and how they work in hospitals, blood establishments, and at a national level. These Chapters are written according to a structured template: products and processes, documentation of jobs, monitoring and assessment, implementation and evaluation of measures for improvement, education and training. Chapters onTrade Review“This is a thoroughly fascinating read and will make you eager to implement or enhance your current hemovigilance efforts. I recommend it.” (Doody’s, 26 April 2013) Table of ContentsList of Contributors, viii Foreword, xii Part 1 General Introduction 1 Introduction, 3 Ren´e R.P. de Vries 2 Hemovigilance: A Quality Tool for the Blood Transfusion Chain, 5 Ren´e R.P. de Vries 3 Concepts and Models, 12 Ren´e R.P. de Vries and Jean-Claude Faber Part 2 Hemovigilance of the Blood Transfusion Chain (Blood Establishment and Hospital) Section 2.1: Setting up a Hemovigilance System 4 Setting Up or Consolidating a System for Donor Hemovigilance at the Level of a Blood Establishment, 21 Johanna Wiersum-Osselton, Wim de Kort, Tanneke Marijt-van der Kreek, and Jeroen de Wit 5 Preparation of Blood Components, 36 Tomislav Vuk 6 Establishment of Hemovigilance for the Testing, Storage, Distribution, Transport, and Issuing of Blood and Blood Components: The Example of Greece, 52 Constantina Politis 7 Medical Decision, Ordering, Administration of Component, and Monitoring of the Patient, 61 Mickey B.C. Koh, Ramir Alcantara, Mark Grumbridge, and Ai Leen Ang Section 2.2: How the System Works 8 Blood Donation: An Approach to Donor Vigilance, 77 Peter Tomasulo, Madhav Erraguntla, and Hany Kamel 9 Preparation of Blood Components, 99 Erhard Seifried, Reinhard Henschler, Juergen Luhm, Thea Mueller-Kuller, Hans-Ulrich Pfeiffer, Walid Sireis, and Markus M. Mueller 10 Testing, Issuing, and Transport of Blood Components, 113 Constantina Politis 11 Clinical Activities: Medical Decision-making, Sampling, Ordering Components, Administration, and Patient Monitoring, 126 Clare Taylor Part 3 National or Regional Hemovigilance Systems 12 The French Hemovigilance Network: From the Blood Scandal to Epidemiologic Surveillance of the Transfusion Chain, 147 Philippe Renaudier 13 The Japanese Hemovigilance System, 159 Hitoshi Okazaki, Naoko Goto, Shun-ya Momose, Satoru Hino, and Kenji Tadokoro 14 Setting up a National Hemovigilance System: SHOT, 168 Hannah Cohen and Lorna M. Williamson 15 The Dutch Hemovigilance System: Transfusion Reactions in Patients (TRIP), 180 Martin R. Schipperus, Johanna Wiersum-Osselton, Pauline Y. Zijlker-Jansen, and Anita J.W. van Tilborgh-de Jong 16 Regulatory, Public Health, and International Aspects of Hemovigilance in Canada, 191 Peter R. Ganz and Jun Wu 17 Setting up and Implementation of the National Hemovigilance System in Italy, 204 Giuliano Grazzini and Simonetta Pupella 18 The Australian Hemovigilance System, 209 Erica M. Wood, Lisa J. Stevenson, Simon A. Brown, and Christopher J. Hogan 19 Biovigilance in the United States, 220 D. Michael Strong, Barbee Whitaker, Matthew J. Kuehnert, and Jerry A. Holmberg 20 Arab Hemovigilance Network, 226 Salwa Hindawi, Magdy Elekiaby, and Gamal Gabra Part 4 Hemovigilance at the International Level 21 Hemovigilance in the European Community, 235 Jean-Claude Faber 22 International collaboration, 253 Paul F.W. Strengers 23 Hemovigilance in Developing Countries, 260 Jean-Claude Faber Part 5 Achievements 24 Achievements Through Hemovigilance, 281 Jean-Claude Faber and F´atima Nascimento Part 6 Developments 25 Vigilance of Alternatives for Blood Components, 305 Dafydd Thomas 26 Surveillance of Clinical Effectiveness of Transfusion, 322 Brian McClelland and Katherine Forrester 27 Biovigilance, 326 Jerry A. Holmberg, Matthew J. Kuehnert, and D. Michael Strong Appendices Appendix A Glossary, 343 Appendix B Proposed standard definitions for surveillance of non infectious adverse transfusion reactions, 351 Appendix C Standard for surveillance of complications related to blood donation, 360 Index, 369

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Book SynopsisVaccinology: An Essential Guide outlines in a clear, practical format the entire vaccine development process, from conceptualization and basic immunological principles through to clinical testing and licensing of vaccines.Trade Review“It can also serve as a useful reference for practicing physicians and veterinarians who would like to “boost” their knowledge of vaccines.” (Clinical Infectious Diseases, 6 October 2015)Table of ContentsContributors vii Preface ix 1 The history of vaccine development and the diseases vaccines prevent 1Martin G. Myers 2 The vaccine development pathway 33David W.C. Beasley 3 Control and eradication of human and animal diseases by vaccination 43Nigel Bourne and Gregg N. Milligan 4 Pathogenesis of infectious diseases and mechanisms of immunity 59Jere W. McBride and David H. Walker 5 The host immune response protective immunity and correlates of protection 73Gregg N. Milligan 6 Adjuvants: making vaccines immunogenic 93Gregg N. Milligan 7 Discovery and the basic science phase of vaccine development 109Gavin C. Bowick 8 Microbial-based and material-based vaccine delivery systems 127Alfredo G. Torres, Jai S. Rudra and Gregg N. Milligan 9 Licensed vaccines for humans 152Alan D.T. Barrett 10 Veterinary vaccines 181A. Paige Adams 11 Development of vaccines for microbial diseases 192Dennis W. Trent and David W.C. Beasley 12 The regulatory path to vaccine licensure 212Dennis W. Trent 13 Veterinary vaccines: regulations and impact on emerging infectious diseases 232A. Paige Adams 14 Vaccine manufacturing 243Dirk E. Teuwen and Alan D.T. Barrett 15 Clinical evaluation of vaccines 260Richard E. Rupp and Bridget E. Hawkins 16 Vaccine recommendations and special populations 273Richard E. Rupp and Bridget E. Hawkins 17 Vaccine safety 287Dirk E. Teuwen and Alan D.T. Barrett 18 Understanding and measuring the dynamics of infectious disease transmission 304Christine M. Arcari 19 Vaccines from a global perspective 319Alan D.T. Barrett and Bridget E. Hawkins 20 Political ethical social and psychological aspects of vaccinology 335Caroline M. Poland, Robert M. Jacobson, Douglas J. Opel, Edgar K. Marcuse and Gregory A. Poland Index 358

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Book SynopsisA comprehensive introduction to inorganic chemistry and, specifically, the science of metal-based drugs, Essentials of Inorganic Chemistry describes the basics of inorganic chemistry, including organometallic chemistry and radiochemistry, from a pharmaceutical perspective. Written for students of pharmacy and pharmacology, pharmaceutical sciences, medicinal chemistry and other health-care related subjects, this accessible text introduces chemical principles with relevant pharmaceutical examples rather than as stand-alone concepts, allowing students to see the relevance of this subject for their future professions. It includes exercises and case studies.Trade Review“It would be a useful adjunct to more general chemistry texts for students in first and second years of study in pharmacy, pharmaceutical sciences, and medicinal chemistry, providing a framework to structure the more detailed but less contextualised information on inorganic pharmaceuticals they will doubtless be looking up on the internet.” (Chemistry in Australia, 1 October 2015)Table of ContentsPreface xiii About the Companion Website xv 1 Introduction 1 1.1 Medicinal inorganic chemistry 1 1.1.1 Why use metal-based drugs? 2 1.2 Basic inorganic principles 3 1.2.1 Electronic structures of atoms 3 1.2.2 Bonds 9 1.3 Exercises 17 References 18 Further Reading 18 2 Alkali Metals 19 2.1 Alkali metal ions 19 2.1.1 Extraction of alkali metals: an introduction to redox chemistry 20 2.1.2 Excursus: reduction – oxidation reactions 21 2.1.3 Chemical behaviour of alkali metals 27 2.2 Advantages and disadvantages using lithium-based drugs 29 2.2.1 Isotopes of lithium and their medicinal application 29 2.2.2 Historical developments in lithium-based drugs 29 2.2.3 The biology of lithium and its medicinal application 30 2.2.4 Excursus: diagonal relationship and periodicity 31 2.2.5 What are the pharmacological targets of lithium? 33 2.2.6 Adverse effects and toxicity 34 2.3 Sodium: an essential ion in the human body 34 2.3.1 Osmosis 35 2.3.2 Active transport of sodium ions 37 2.3.3 Drugs, diet and toxicity 38 2.4 Potassium and its clinical application 40 2.4.1 Biological importance of potassium ions in the human body – action potential 40 2.4.2 Excursus: the Nernst equation 40 2.4.3 Potassium salts and their clinical application: hypokalaemia 42 2.4.4 Adverse effects and toxicity: hyperkalaemia 43 2.5 Exercises 45 2.6 Case studies 47 2.6.1 Lithium carbonate (Li2CO3) tablets 47 2.6.2 Sodium chloride eye drops 47 References 48 Further Reading 48 3 Alkaline Earth Metals 49 3.1 Earth alkaline metal ions 49 3.1.1 Major uses and extraction 50 3.1.2 Chemical properties 51 3.2 Beryllium and chronic beryllium disease 52 3.3 Magnesium: competition to lithium? 53 3.3.1 Biological importance 53 3.3.2 Clinical applications and preparations 54 3.4 Calcium: the key to many human functions 55 3.4.1 Biological importance 56 3.4.2 How does dietary calcium intake influence our lives? 57 3.4.3 Calcium deficiency: osteoporosis, hypertension and weight management 57 3.4.4 Renal osteodystrophy 58 3.4.5 Kidney stones 59 3.4.6 Clinical application 59 3.4.7 Side effects 61 3.5 Barium: rat poison or radio-contrast agent? 61 3.6 Exercises 63 3.7 Case studies 65 3.7.1 Magnesium hydroxide suspension 65 3.7.2 Calcium carbonate tablets 65 References 66 Further Reading 66 4 The Boron Group – Group 13 67 4.1 General chemistry of group 13 elements 67 4.1.1 Extraction 68 4.1.2 Chemical properties 69 4.2 Boron 70 4.2.1 Introduction 70 4.2.2 Pharmaceutical applications of boric acid 71 4.2.3 Bortezomib 71 4.3 Aluminium 71 4.3.1 Introduction 71 4.3.2 Biological importance 72 4.3.3 Al3+ and its use in water purification 73 4.3.4 Aluminium-based adjuvants 73 4.3.5 Antacids 74 4.3.6 Aluminium-based therapeutics – alginate raft formulations 75 4.3.7 Phosphate binders 76 4.3.8 Antiperspirant 76 4.3.9 Potential aluminium toxicity 77 4.4 Gallium 77 4.4.1 Introduction 77 4.4.2 Chemistry 77 4.4.3 Pharmacology of gallium-based drugs 78 4.4.4 Gallium nitrate – multivalent use 78 4.4.5 Gallium 8-quinolinolate 79 4.4.6 Gallium maltolate 79 4.4.7 Toxicity and administration 80 4.5 Exercises 81 4.6 Case studies 83 4.6.1 Boric acid – API analysis 83 4.6.2 Aluminium hydroxide tablets 83 References 84 Further Reading 84 5 The Carbon Group 85 5.1 General chemistry of group 14 elements 85 5.1.1 Occurrence, extraction and use of group 14 elements 85 5.1.2 Oxidation states and ionisation energies 87 5.1.3 Typical compounds of group 14 elements 87 5.2 Silicon-based drugs versus carbon-based analogues 89 5.2.1 Introduction of silicon groups 90 5.2.2 Silicon isosters 91 5.2.3 Organosilicon drugs 93 5.3 Organogermanium compounds: balancing act between an anticancer drug and a herbal supplement 94 5.3.1 Germanium sesquioxide 95 5.3.2 Spirogermanium 97 5.4 Exercises 99 5.5 Cases studies 101 5.5.1 Simethicone 101 5.5.2 Germanium supplements 101 References 102 Further Reading 102 6 Group 15 Elements 103 6.1 Chemistry of group 15 elements 103 6.1.1 Occurrence and extraction 103 6.1.2 Physical properties 104 6.1.3 Oxidation states and ionisation energy 105 6.1.4 Chemical properties 106 6.2 Phosphorus 106 6.2.1 Adenosine phosphates: ATP, ADP and AMP 107 6.2.2 Phosphate in DNA 107 6.2.3 Clinical use of phosphate 108 6.2.4 Drug interactions and toxicity 112 6.3 Arsenic 112 6.3.1 Salvarsan: the magic bullet – the start of chemotherapy 113 6.3.2 Arsenic trioxide: a modern anticancer drug? 116 6.4 Exercises 119 6.5 Case studies 121 6.5.1 Phosphate solution for rectal use 121 6.5.2 Forensic test for arsenic 121 References 122 Further Reading 122 7 Transition Metals and d-Block Metal Chemistry 123 7.1 What are d-block metals? 123 7.1.1 Electronic configurations 123 7.1.2 Characteristic properties 124 7.1.3 Coordination numbers and geometries 125 7.1.4 Crystal field theory 129 7.2 Group 10: platinum anticancer agents 132 7.2.1 Cisplatin 134 7.2.2 Platinum anticancer agents 140 7.3 Iron and ruthenium 147 7.3.1 Iron 148 7.3.2 Ruthenium 155 7.4 The coinage metals 159 7.4.1 General chemistry 159 7.4.2 Copper-containing drugs 160 7.4.3 Silver: the future of antimicrobial agents? 163 7.4.4 Gold: the fight against rheumatoid arthritis 165 7.5 Group 12 elements: zinc and its role in biological systems 168 7.5.1 General chemistry 169 7.5.2 The role of zinc in biological systems 170 7.5.3 Zinc: clinical applications and toxicity 173 7.6 Exercises 177 7.7 Case studies 179 7.7.1 Silver nitrate solution 179 7.7.2 Ferrous sulfate tablets 179 7.7.3 Zinc sulfate eye drops 180 References 181 Further Reading 181 8 Organometallic Chemistry 183 8.1 What is organometallic chemistry? 183 8.2 What are metallocenes? 185 8.3 Ferrocene 187 8.3.1 Ferrocene and its derivatives as biosensors 188 8.3.2 Ferrocene derivatives as potential antimalarial agent 189 8.3.3 Ferrocifen – a new promising agent against breast cancer? 191 8.4 Titanocenes 194 8.4.1 History of titanium-based anticancer agents: titanocene dichloride and budotitane 195 8.4.2 Further developments of titanocenes as potential anticancer agents 197 8.5 Vanadocenes 200 8.5.1 Vanadocene dichloride as anticancer agents 202 8.5.2 Further vanadium-based drugs: insulin mimetics 203 8.6 Exercises 207 8.7 Case study – titanium dioxide 209 References 210 Further Reading 210 9 The Clinical Use of Lanthanoids 211 9.1 Biology and toxicology of lanthanoids 211 9.2 The clinical use of lanthanum carbonate 213 9.3 The clinical application of cerium salts 214 9.4 The use of gadolinium salts as MRI contrast agents 215 9.5 Exercises 219 9.6 Case study: lanthanum carbonate tablets 221 References 222 Further Reading 222 10 Radioactive Compounds and Their Clinical Application 223 10.1 What is radioactivity? 223 10.1.1 The atomic structure 223 10.1.2 Radioactive processes 224 10.1.3 Radioactive decay 224 10.1.4 Penetration potential 227 10.1.5 Quantification of radioactivity 227 10.2 Radiopharmacy: dispensing and protection 232 10.3 Therapeutic use of radiopharmaceuticals 233 10.3.1 131Iodine: therapy for hyperthyroidism 233 10.3.2 89Strontium 234 10.3.3 Boron neutron capture therapy (BNCT) 235 10.4 Radiopharmaceuticals for imaging 235 10.4.1 99mTechnetium 237 10.4.2 18Fluoride: PET scan 240 10.4.3 67Gallium: PET 241 10.4.4 201Thallium 242 10.5 Exercises 245 10.6 Case studies 247 10.6.1 A sample containing 99mTc was found to have a radioactivity of 15 mCi at 8 a.m. when the sample was tested. 247 10.6.2 A typical intravenous dose of 99mTc-albumin used for lung imaging contains a radioactivity of 4 mCi 247 10.6.3 Develop a quick-reference radioactive decay chart for 131I 247 References 248 Further Reading 248 11 Chelation Therapy 249 11.1 What is heavy-metal poisoning? 249 11.2 What is chelation? 250 11.3 Chelation therapy 252 11.3.1 Calcium disodium edetate 252 11.3.2 Dimercaprol (BAL) 253 11.3.3 Dimercaptosuccinic acid (DMSA) 254 11.3.4 2,3-Dimercapto-1-propanesulfonic acid (DMPS) 254 11.3.5 Lipoic acid (ALA) 254 11.4 Exercises 257 11.5 Case studies 259 11.5.1 Disodium edetate 259 11.5.2 Dimercaprol 259 References 261 Further Reading 261 Index 263

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Book SynopsisThis book aims to be a guide to the practice of blood conservation. The first chapter discusses the legal and administrative aspects of bloodless medicine describing the legal principles and practical issues relatd to refusal of transfusion. The second is on balancing the risks and benefits of transfusion includes clinical vignettes of appropriate and inappropriate transfusion. The remainder of the book covers the principles and practice of bloodless medicine, including a chapter on the scientific issues of haemostasis and the investigation of bleeding idsorders. The book concludes with chapters on blood conservation in neonatal and paediatric surgery, the costs associated with blood transfusion and the quest for artifical blood. New chapters will be included to address blood utilization in oncology and geriatric patients.Table of ContentsContributors, ix Preface, xiii 1 History of blood transfusion and patient blood management, 1 Shannon L. Farmer, James Isbister, and Michael F. Leahy 2 The ethical complexities of transfusion-free medicine, surgery and research, 19 Katrina A. Bramstedt 3 Transfusion therapy – Balancing the risks and benefits, 28 Irina Maramica and Ira A. Shulman 4 The physiology of anemia and the threshold for blood transfusion, 61 Senthil G. Krishna, Ahsan Syed, Jason Bryant, and Joseph D. Tobias 5 Blood transfusion in surgery, 83 Sharad Sharma, Lance W Griffin, and Nicolas Jabbour 6 Current view of coagulation system, 102 Yoogoo Kang and Elia Elia 7 Topical hemostatic agents, 143 Fabrizio Di Benedetto and Giuseppe Tarantino 8 Intraoperative strategies for transfusion-free medicine, 158 Joseph D. Tobias 9 Post-operative management in transfusion-free medicine and surgery in the ICU, 207 Jean-Louis Vincent 10 The changing transfusion practice of neonatal and pediatric surgery, 222 Pamela J. Kling and Nicolas Jabbour 11 Current management of anemia in oncology, 247 Shelly Sharma and Sharad Sharma 12 Artificial blood, 271 Aryeh Shander, Mazyar Javidroozi, and Seth Perelman 13 Translational strategies to minimize transfusion requirement in liver surgery and transplantation: Targeting ischemia-reperfusion injury, 289 Reza F. Saidi and S. Kamran Hejazi Kenari 14 Legal and administrative issues related to transfusion-free medicine and surgery programs, 315 Randy Henderson and Nicolas Jabbour 15 Basic principles of bloodless medicine and surgery, 338 Nicolas Jabbour Index, 347

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Book SynopsisMany newly proposed drugs suffer from poor water solubility, thus presenting major hurdles in the design of suitable formulations for administration to patients. Consequently, the development of techniques and materials to overcome these hurdles is a major area of research in pharmaceutical companies. Drug Delivery Strategies for Poorly Water-Soluble Drugs provides a comprehensive overview of currently used formulation strategies for hydrophobic drugs, including liposome formulation, cyclodextrin drug carriers, solid lipid nanoparticles, polymeric drug encapsulation delivery systems, selfmicroemulsifying drug delivery systems, nanocrystals, hydrosol colloidal dispersions, microemulsions, solid dispersions, cosolvent use, dendrimers, polymer- drug conjugates, polymeric micelles, and mesoporous silica nanoparticles. For each approach the book discusses the main instrumentation, operation principles and theoretical background, with a focus on critical formulation feaTable of ContentsList of Contributors xvii Series Preface xxi Preface xxiii 1 Self-Assembled Delivery Vehicles for Poorly Water-Soluble Drugs: Basic Theoretical Considerations and Modeling Concepts 1 Sylvio May and Alfred Fahr 1.1 Introduction 1 1.2 Brief Reminder of Equilibrium Thermodynamics 3 1.3 Principles of Self-Assembly in Dilute Solutions 7 1.3.1 Linear Growth 9 1.3.2 Cooperative Assembly 10 1.4 Solubility and Partitioning of Drugs 11 1.4.1 Simple Partitioning Equilibria 11 1.4.2 Partitioning and Micellization 13 1.4.3 Hydrophobicity and Ordering of Water 15 1.5 Ways to Model Interactions in Colloidal Systems 16 1.5.1 Electrostatic Interactions: The Poisson–Boltzmann Model 17 1.5.2 Chain Packing Model 21 1.6 Kinetics of Drug Transfer from Mobile Nanocarriers 23 1.6.1 Collision Mechanism 25 1.6.2 Diffusion Mechanism 26 1.6.3 Internal Kinetics 26 1.7 Conclusion 29 Acknowledgments 31 References 31 2 Liposomes as Intravenous Solubilizers for Poorly Water-Soluble Drugs 37 Peter van Hoogevest, Mathew Leigh and Alfred Fahr 2.1 Introduction 37 2.2 Intravenous Administration of Poorly Water-Soluble Compounds (PWSC) 40 2.2.1 Solubilizing Vehicles with Precipitation Risk upon Dilution 41 2.2.2 Solubilizing Vehicles Maintaining Solubilization Capacity upon Dilution 43 2.2.3 Mechanistic Release Aspects/Transfer Liposomal PWSC 45 2.2.4 In Vivo Consequences 52 2.2.5 Preclinical Parenteral Assessment Liposomal PWSC 56 2.3 Conclusion 59 References 60 3 Drug Solubilization and Stabilization by Cyclodextrin Drug Carriers 67 Thorsteinn Loftsson and Marcus E. Brewster 3.1 Introduction 67 3.2 Structure and Physiochemical Properties 68 3.3 Cyclodextrin Complexes and Phase Solubility Diagrams 72 3.4 Cyclodextrin Complexes 76 3.4.1 Self-Assembly of Cyclodextrins and their Complexes 76 3.4.2 Thermodynamic and Driving Forces for Complexation 76 3.5 Effects on Drug Stability 77 3.6 Cyclodextrins and Drug Permeation through Biological Membranes 80 3.7 Drug Solubilization in Pharmaceutical Formulations 82 3.7.1 Oral Drug Delivery 84 3.7.2 Sublingual, Buccal, Nasal, Pulmonary, Rectal and Vaginal Drug Delivery 86 3.7.3 Ophthalmic Drug Delivery 87 3.7.4 Dermal and Transdermal Drug Delivery 87 3.7.5 Injectable Formulations 87 3.8 Toxicology and Pharmacokinetics 89 3.9 Regulatory Issues 90 3.10 Conclusion 91 References 91 4 Solid Lipid Nanoparticles for Drug Delivery 103 Sonja Joseph and Heike Bunjes 4.1 Introduction 103 4.2 Preparation Procedures for Solid Lipid Nanoparticles 104 4.2.1 Melt Dispersion Processes 104 4.2.2 Other Top-Down Processes 109 4.2.3 Precipitation from Homogeneous Systems 111 4.2.4 Comparison of the Formulation Procedures and Scale-Up Feasibility 113 4.2.5 Further Processing of Solid Lipid Nanoparticle Suspensions 115 4.3 Structural Parameters and Their Influence on Product Quality and Pharmaceutical Performance 116 4.3.1 Particle Size and Size Distribution 116 4.3.2 Surface Properties 117 4.3.3 Solid State Properties of Solid Lipid Nanoparticles 117 4.3.4 Particle Morphology and Overall Structure of the Dispersions 121 4.4 Incorporation of Poorly Soluble Drugs and In Vitro Release 123 4.4.1 Drug Incorporation 123 4.4.2 In Vitro Drug Release 126 4.5 Safety Aspects, Toxicity and Pharmacokinetic Profiles 129 4.5.1 In Vitro Behavior and Toxicity Studies 129 4.5.2 Bioavailability and Pharmacokinetics 131 4.6 Conclusion 133 References 133 5 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 151 Naveed Ahmed, C.E. Mora-Huertas, Chiraz Jaafar-Maalej, Hatem Fessi and Abdelhamid Elaissari 5.1 Introduction 151 5.2 Safety and Biocompatibility of Polymers 152 5.3 Encapsulation Techniques of Hydrophobic Drugs 156 5.3.1 The Nanoprecipitation Method 156 5.3.2 The Emulsification Methods 158 5.3.3 Polymersome Preparation 164 5.3.4 Supercritical Fluid Technology 166 5.3.5 The Polymer-Coating Method 167 5.3.6 The Layer-by-Layer Method 171 5.4 Behavior of Nanoparticles as Drug Delivery Systems 173 5.4.1 Mean Size 173 5.4.2 Zeta Potential 173 5.4.3 Encapsulation Efficiency 174 5.4.4 Drug Release Properties 176 5.4.5 General Performance of the Nanoparticles 176 5.5 Conclusion 177 References 180 6 Polymeric Drug Delivery Systems for Encapsulating Hydrophobic Drugs 199 Dagmar Fischer 6.1 Introduction 199 6.2 Drug Encapsulation by Monomer Polymerization 200 6.2.1 Emulsion Polymerization 201 6.2.2 Interfacial Polymerization 206 6.2.3 Interfacial Polycondensation 207 6.3 Polymeric Nanospheres and Nanocapsules Produced by Polymerization 209 6.4 Formulation Components 210 6.5 Control of Particle Morphology 212 6.6 Toxicity and In Vivo Performance 213 6.7 Scale-Up Considerations 214 6.8 Conclusion 217 Acknowledgements 217 References 217 7 Development of Self-Emulsifying Drug Delivery Systems (SEDDS) for Oral Bioavailability Enhancement of Poorly Soluble Drugs 225 Dimitrios G. Fatouros and Anette M¨ullertz 7.1 Introduction 225 7.2 Lipid Processing and Drug Solubilization 226 7.3 Self-Emulsifying Drug Delivery Systems 227 7.3.1 Excipients Used in SEDDS 227 7.3.2 Self-Emulsification Mechanism 228 7.3.3 Physicochemical Characterization of SEDDS 229 7.3.4 Drug Incorporation in SEDDS 231 7.4 In Vitro Digestion Model 232 7.5 Enhancement of Oral Absorption by SEDDS 235 7.6 Conclusion 238 References 239 8 Novel Top-Down Technologies: Effective Production of Ultra-Fine Drug Nanocrystals 247 C.M. Keck, S. Kobierski, R. Mauludin and R.H. M¨uller 8.1 Introduction: General Benefits of Drug Nanocrystals (First Generation) 247 8.2 Ultra-Fine Drug Nanocrystals (_100 Nm) and Their Special Properties 248 8.3 Production of First Generation Nanocrystals: A Brief Overview 250 8.3.1 Hydrosols 250 8.3.2 Nanomorphs 251 8.3.3 NanocrystalsTM by Bead Milling 251 8.3.4 DissoCubes R _ by High Pressure Homogenization 251 8.3.5 NANOEDGE by Baxter 252 8.3.6 Summary of First Generation Production Technologies 252 8.4 Production of Ultra-Fine Drug Nanocrystals: Smartcrystals 252 8.4.1 Fine-Tuned Precipitation 252 8.4.2 The SmartCrystal Concept 253 8.5 Conclusion 259 References 259 9 Nanosuspensions with Enhanced Drug Dissolution Rates of Poorly Water-Soluble Drugs 265 Dennis Douroumis 9.1 Introduction 265 9.2 Crystal Growth and Nucleation Theory 266 9.3 Creating Supersaturation and Stable Nanosuspensions 269 9.4 Antisolvent Precipitation Via Mixer Processing 272 9.5 Antisolvent Precipitation by Using Ultrasonication 277 9.6 Nanoprecipitation Using Microfluidic Reactors 278 9.7 Particle Engineering by Spray: Freezing into Liquid 279 9.8 Precipitation by Rapid Expansion from Supercritical to Aqueous Solution 280 9.9 Conclusion 282 References 283 10 Microemulsions for Drug Solubilization and Delivery 287 X.Q. Wang and Q. Zhang 10.1 Introduction 287 10.2 Microemulsion Formation and Phase Behavior 289 10.2.1 Theories of Microemulsion Formation 289 10.2.2 Structure of Microemulsions 289 10.2.3 Phase Behavior 292 10.3 HLB, PIT and Microemulsion Stability 293 10.4 Microemulsion Physico-Chemical Characterization 293 10.5 Components of Microemulsion Formulations 295 10.5.1 Oils 296 10.5.2 Surfactants 298 10.5.3 Cosurfactants 300 10.5.4 Drugs 302 10.6 Preparation Methods 303 10.7 In Vitro and In Vivo Biological Studies 303 10.7.1 Microemulsions Used as an Oral Delivery System for Poorly Water-Soluble Compounds 303 10.7.2 Microemulsions Used as a Parenteral Delivery System for Poorly Water-Soluble Compounds 311 10.8 Recent Developments and Future Directions 314 10.8.1 Develop Cremophor-Free Microemulsions 314 10.8.2 Dried O/W Emulsions for Oral Delivery of Poorly Soluble Drugs 315 10.8.3 Self-Microemulsifying Drug Delivery System (SMEDDS) 318 References 319 11 Hot Melt Extrusion: A Process Overview and Use in Manufacturing Solid Dispersions of Poorly Water-Soluble Drugs 325 Shu Li, David S. Jones and Gavin P. Andrews 11.1 Introduction: Present Challenges to Oral Drug Delivery 325 11.2 Solid Drug Dispersions for Enhanced Drug Solubility 327 11.3 Hot Melt Extrusion (HME) as a Drug Delivery Technology 329 11.3.1 Historical Review of HME 329 11.3.2 Equipment 329 11.3.3 Screw Geometry 331 11.3.4 HME Processing 332 11.3.5 Product Characteristics 335 11.3.6 Materials Commonly Used in HME for Solubility Enhancement 337 11.4 Solubility Enhancement Using HME 340 11.4.1 Product Structure 340 11.4.2 HME Matrix Carriers 341 11.4.3 HME for the Manufacture of Pharmaceutical Co-Crystals 343 11.5 Representative Case Studies with Enhanced Solubility 344 11.5.1 Increased Dissolution Rate Due to Size Reduction or De-Aggregation 344 11.5.2 Increased Dissolution Rate Due to Drug Morphology Change 345 11.5.3 Controlled or Prolonged Release with Enhanced Release Extent 346 11.5.4 Complexation to Enhance Dissolution Performance 346 11.5.5 Co-Crystal Formation 347 11.6 Conclusion 347 References 348 12 Penetration Enhancers, Solvents and the Skin 359 Jonathan Hadgraft and Majella E. Lane 12.1 Introduction 359 12.2 Interactions of Solvents and Enhancers with the Skin 360 12.2.1 Small Solvents 361 12.2.2 Solvents with Longer Carbon Chains 361 12.3 Skin Permeation Enhancement of Ibuprofen 363 12.3.1 Infinite Dose Conditions 364 12.3.2 Finite Dose Conditions 368 12.4 Conclusion 369 References 369 13 Dendrimers for Enhanced Drug Solubilization 373 Narendra K. Jain and Rakesh K. Tekade 13.1 Introduction 373 13.2 Current Solubilization Strategies 374 13.3 Origin of Dendrimers 374 13.4 What Are Dendrimers? 375 13.5 Synthesis of Dendritic Architecture 375 13.6 Structure and Intrinsic Properties of Dendrimeric Compartments 377 13.7 Dendrimers in Solubilization 378 13.8 Factors Affecting Dendrimer-Mediated Solubilization and Drug Delivery 381 13.8.1 Nature of the Dendritic Core 381 13.8.2 Dendrimer Generation 382 13.8.3 Nature of the Dendrimer Surface 382 13.8.4 Dendrimer Concentration 382 13.8.5 pH of Solution 383 13.8.6 Temperature 384 13.8.7 Solvents 384 13.9 Drug–Dendrimer Conjugation Approaches 386 13.9.1 Physical Loading: Complexation of Water-Insoluble Drugs 386 13.9.2 Covalent Loading: Synthesis of Drug–Dendrimer Conjugate 389 13.10 Dendrimers’ Biocompatibility and Toxicity 393 13.10.1 PEGylation Technology: A Way to Enhance Dendrimer Solubility and Biocompatibility 393 13.11 Classification of PEGylated Dendrimers 394 13.11.1 PEGylated Dendrimer 394 13.11.2 Drug-Conjugated PEGylated Dendrimer 397 13.11.3 PEG Cored Dendrimer 397 13.11.4 PEG Branched Dendrimer 398 13.11.5 PEG-Conjugated Targeted Dendrimer 398 13.12 Conclusion 399 References 400 14 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 411 Swati Biswas, Onkar S. Vaze, Sara Movassaghian and Vladimir P. Torchilin 14.1 Micelles and Micellization 411 14.1.1 Factors Affecting Micellization 413 14.1.2 Thermodynamics of Micellization 414 14.2 Chemical Nature and Formation Mechanism of Polymeric Micelles 416 14.2.1 Core and Corona of the Polymeric Micelles 417 14.2.2 Block Co-Polymers as Building Block of Polymeric Micelles 418 14.3 Polymeric Micelles: Unique Nanomedicine Platforms 419 14.3.1 Polymeric Micelles for the Delivery of Poorly Soluble Drugs 421 14.4 Determination of Physico-Chemical Characteristics of Polymeric Micelles 430 14.4.1 Critical Micelle Concentrations (CMC) 430 14.4.2 Particle Size and Stability 432 14.5 Drug Loading 435 14.5.1 Drug-Loading Procedures 437 14.6 Biodistribution and Toxicity 439 14.7 Targeting Micellar Nanocarriers: Example: Drug Delivery to Tumors 443 14.7.1 Passive Targeting 443 14.7.2 Active Targeting: Functionalized Polymeric Micelles 445 14.8 Site-Specific Micellar-Drug Release Strategies 449 14.9 Intracellular Delivery of Micelles 452 14.10 Multifunctional Micellar Nanocarriers 453 14.11 Conclusion 455 References 455 15 Nanostructured Silicon-Based Materials as a Drug Delivery System for Water-Insoluble Drugs 477 Vesa-Pekka Lehto, Jarno Salonen, H´elder A. Santos and Joakim Riikonen 15.1 Introduction 477 15.2 Control of Particle Size and Pore Morphology 478 15.3 Surface Functionalization 482 15.3.1 Stabilization 482 15.3.2 Biofunctionalization 483 15.4 Biocompatibility and Cytotoxicity 485 15.4.1 In Vitro Studies 486 15.4.2 In Vivo and Ex Vivo Studies 490 15.5 Nanostructured Silicon Materials as DDS 492 15.5.1 Drug-Loading Procedures 492 15.5.2 Enhanced Drug Release 495 15.5.3 Intracellular Uptake 500 15.6 Conclusion 502 References 502 16 Micro- and Nanosizing of Poorly Soluble Drugs by Grinding Techniques 509 Stefan Scheler 16.1 Introduction 509 16.2 Kinetics of Drug Dissolution 510 16.3 Micronization and Nanosizing of Drugs 510 16.3.1 Dissolution Enhancement by Micronization and Nanonization 510 16.3.2 Dry and Wet Milling Technologies 511 16.3.3 NanoCrystal R _ Technology 512 16.4 Theory of Grinding Operations 512 16.4.1 Fraction under Compressive Stress 512 16.4.2 Brittle-Ductile Transition and Grinding Limit 514 16.4.3 Milling Beyond the Brittle-Ductile Transition Limit 516 16.4.4 Fatigue Fracture 517 16.4.5 Agglomeration 517 16.4.6 Amorphization 519 16.5 Influence of the Stabilizer 520 16.5.1 Effects of Stabilization 520 16.5.2 Steric and Electrostatic Stabilization 521 16.5.3 Surfactants 523 16.5.4 Polymers 527 16.6 Milling Equipment and Technology 527 16.6.1 Grinding Beads 527 16.6.2 Types of Media Mills 528 16.6.3 Process Parameters 532 16.7 Process Development from Laboratory to Commercial Scale 535 16.7.1 Early Development 535 16.7.2 Toxicological Studies 535 16.7.3 Clinical Studies 536 16.7.4 Drying 536 16.7.5 Further Processing of Drug Nanoparticles 536 16.8 Application and Biopharmaceutical Properties 537 16.8.1 Oral Drug Delivery 538 16.8.2 Parenteral Drug Delivery 540 16.8.3 Extracorporal Therapy 542 16.9 Conclusion 543 References 543 17 Enhanced Solubility of Poorly Soluble Drugs Via Spray Drying 551 Cordin Arpagaus, David R¨utti and Marco Meuri 17.1 Introduction 551 17.2 Advantages of Spray Drying 553 17.3 Principles and Instrumentation of Spray Drying Processes 553 17.3.1 Principal Function of a Spray Dryer 553 17.3.2 Traditional Spray Dryers 558 17.3.3 Recent Developments in Spray Drying 561 17.4 Optimizing Spray Drying Process Parameters 563 17.4.1 Drying Gas Flow Rate (Aspirator Rate) 563 17.4.2 Drying Gas Humidity 563 17.4.3 Inlet Temperature 564 17.4.4 Spray Gas Flow 565 17.4.5 Feed Concentration 565 17.4.6 Feed Rate 565 17.4.7 Organic Solvent Instead of Water 566 17.5 Spray Drying of Water-Insoluble Drugs: Case Studies 566 17.5.1 Nanosuspensions 566 17.5.2 Solid Lipid Nanoparticles 568 17.5.3 Silica-Lipid Hybrid Microcapsules 568 17.5.4 Milled Nanoparticles 570 17.5.5 Inhalation Dosage Forms 571 17.5.6 Porous Products 572 17.5.7 Microemulsions 572 17.5.8 Application Examples: Summary 575 17.6 Conclusion 582 References 583 Index 587

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Book SynopsisThe latest edition of this highly acclaimed textbook, provides a comprehensive and up--to--date overview of the science and medical applications of biopharmaceutical products.Trade Review"…contains just about everything that anyone would want to know about the subject…It's all here in this easy-to-read textbook.” (Biochemistry and Molecular Education, March/April 2004) "...well written… (and) copiously illustrated..." (Chemistry & Industry, 17th January 2005) “This book should be recommended reading for all under-graduate course in pharmacy and the pharmaceutical sciences …”. (Cell Biochemistry & Function, March-April 2005)Table of ContentsPreface xvii Chapter 1 Pharmaceuticals, biologics and biopharmaceuticals 1 Introduction to pharmaceutical products 1 Biopharmaceuticals and pharmaceutical biotechnology 1 History of the pharmaceutical industry 3 The age of biopharmaceuticals 5 Biopharmaceuticals: current status and future prospects 8 Traditional pharmaceuticals of biological origin 12 Pharmaceuticals of animal origin 13 The sex hormones 14 The androgens 14 Oestrogens 15 Progesterone and progestogens 17 Corticosteroids 19 Catecholamines 21 Prostaglandins 23 Pharmaceutical substances of plant origin 27 Alkaloids 28 Atropine and scopalamine 28 Morphine and cocaine 29 Additional plant alkaloids 30 Ergot alkaloids 30 Flavonoids, xanthines and terpenoids 30 Cardiac glycosides and coumarins 33 Aspirin 33 Pharmaceutical substances of microbial origin 33 The macrolides and ansamycins 38 Peptide and other antibiotics 39 Conclusion 39 Further reading 40 Chapter 2 The drug development process 43 Drug discovery 44 The impact of genomics and related technologies upon drug discovery 45 Gene chips 47 Proteomics 49 Structural genomics 50 Pharmacogenetics 51 Plants as a source of drugs 52 Microbial drugs 53 Rational drug design 54 Combinatorial approaches to drug discovery 56 Initial product characterization 57 Patenting 57 What is a patent and what is patentable? 57 Patent types 62 The patent application 63 Patenting in biotechnology 64 Delivery of biopharmaceuticals 66 Oral delivery systems 66 Pulmonary delivery 67 Nasal, transmucosal and transdermal delivery systems 68 Pre-clinical trials 69 Pharmacokinetics and pharmacodynamics 69 Toxicity studies 71 Reproductive toxicity and teratogenicity 71 Mutagenicity, carcinogenicity and other tests 72 Clinical trials 73 Clinical trial design 75 Trial size and study population 75 Randomized control studies 76 Additional trial designs 76 The role and remit of regulatory authorities 78 The Food and Drug Administration 78 The investigational new drug application 80 The new drug application 82 European regulations 84 National regulatory authorities 84 The EMEA and the new EU drug approval systems 85 The centralized procedure 86 Mutual recognition 88 Drug registration in Japan 88 World harmonization of drug approvals 89 Conclusion 89 Further reading 89 Chapter 3 The drug manufacturing process 93 International pharmacopoeia 93 Martindale, the Extra Pharmacopoeia 94 Guides to good manufacturing practice 94 The manufacturing facility 97 Clean rooms 98 Cleaning, decontamination and sanitation (CDS) 101 CDS of the general manufacturing area 102 CDS of process equipment 102 Water for biopharmaceutical processing 104 Generation of purified water and water for injections (WFI) 105 Distribution system for WFI 107 Documentation 109 Specifications 110 Manufacturing formulae, processing and packaging instructions 110 Records 111 Generation of manufacturing records 111 Sources of biopharmaceuticals 112 E. coli as a source of recombinant, therapeutic proteins 112 Expression of recombinant proteins in animal cell culture systems 116 Additional production systems: yeasts 116 Fungal production systems 117 Transgenic animals 118 Transgenic plants 122 Insect cell-based systems 123 Production of final product 124 Cell banking systems 127 Upstream processing 128 Microbial cell fermentation 129 Mammalian cell culture systems 133 Downstream processing 134 Final product formulation 140 Some influences that can alter the biological activity of proteins 142 Proteolytic degradation 143 Protein deamidation 144 Oxidation and disulphide exchange 145 Alteration of glycoprotein glycosylation patterns 147 Stabilizing excipients used in final product formulations 150 Final product fill 153 Freeze-drying 155 Labelling and packing 158 Analysis of the final product 159 Protein-based contaminants 159 Removal of altered forms of the protein of interest from the product stream 160 Product potency 161 Determination of protein concentration 163 Detection of protein-based product impurities 164 Capillary electrophoresis 166 High-pressure liquid chromatography (HPLC) 167 Mass spectrometry 168 Immunological approaches to detection of contaminants 168 Amino acid analysis 169 Peptide mapping 170 N-terminal sequencing 171 Analysis of secondary and tertiary structure 173 Endotoxin and other pyrogenic contaminants 173 Endotoxin, the molecule 174 Pyrogen detection 176 Dna 179 Microbial and viral contaminants 180 Viral assays 181 Miscellaneous contaminants 182 Validation studies 183 Further reading 185 Chapter 4 The cytokines —the interferon family 189 Cytokines 189 Cytokine receptors 194 Cytokines as biopharmaceuticals 195 The interferons 196 The biochemistry of interferon-a 197 Interferon-b 198 Interferon-g 198 Interferon signal transduction 198 The interferon receptors 199 The JAK–STAT pathway 199 The interferon JAK–STAT pathway 202 The biological effects of interferons 203 The eIF-2a protein kinase system 207 Interferon biotechnology 207 Production and medical uses of IFN-a 210 Medical uses of IFN-b 213 Medical applications of IFN-g 214 Interferon toxicity 216 Additional interferons 218 Conclusion 219 Further reading 219 Chapter 5 Cytokines: interleukins and tumour necrosis factor 223 Interleukin-2 (IL-2) 225 IL-2 production 228 IL-2 and cancer treatment 228 IL-2 and infectious diseases 230 Safety issues 231 Inhibition of IL-2 activity 231 Interleukin-1 (IL-1) 232 The biological activities of IL- 1 233 IL-1 biotechnology 234 Interleukin-3: biochemistry and biotechnology 235 Interleukin- 4 236 Interleukin- 6 238 Interleukin- 11 240 Interleukin- 5 241 Interleukin- 12 244 Tumour necrosis factors (TNFs) 246 TNF biochemistry 246 Biological activities of TNF-a 247 Immunity and inflammation 248 TNF receptors 249 TNF: therapeutic aspects 250 Further reading 252 Chapter 6 Haemopoietic growth factors 255 The interleukins as haemopoietic growth factors 257 Granulocyte colony stimulating factor (G-CSF) 258 Macrophage colony-stimulating factor (M-CSF) 259 Granulocyte-macrophage colony stimulating factor (GM-CSF) 259 Clinical application of CSFs 261 Leukaemia inhibitory factor (LIF) 263 Erythropoietin (EPO) 264 The EPO receptor and signal transduction 267 Regulation of EPO production 267 Therapeutic applications of EPO 268 Chronic disease and cancer chemotherapy 271 Additional non-renal applications 272 Tolerability 273 Thrombopoietin 273 Further reading 275 Chapter 7 Growth factors 277 Growth factors and wound healing 277 Insulin-like growth factors (IGFs) 279 IGF biochemistry 280 IGF receptors 280 IGF-binding proteins 282 Biological effects 282 IGF and fetal development 283 IGFs and growth 283 Renal and reproductive effects 284 Neuronal and other effects 285 Epidermal growth factor (EGF) 285 The EGF receptor 286 Platelet-derived growth factor (PDGF) 287 The PDGF receptor and signal transduction 288 PDGF and wound healing 289 Fibroblast growth factors (FGFs) 289 Transforming growth factors (TGFs) 290 TGF-a 290 TGF-b 292 Neurotrophic factors 293 The neurotrophins 294 Neurotrophin receptors 296 The neurotrophin low-affinity receptor 297 Ciliary neurotrophic factor and glial cell line-derived neurotrophic factor 297 Neurotrophic factors and neurodegenerative disease 298 Amyotrophic lateral sclerosis (ALS) and peripheral neuropathy 298 Neurotrophic factors and neurodegenerative diseases of the brain 298 Further reading 300 Chapter 8 Hormones of therapeutic interest 303 Insulin 303 Diabetes mellitus 304 The insulin molecule 304 The insulin receptor and signal transduction 307 Insulin production 307 Enzymatic conversion of porcine insulin 311 Production of human insulin by recombinant DNA technology 312 Formulation of insulin products 314 Engineered insulins 317 Additional means of insulin administration 320 Treating diabetics with insulin-producing cells 321 Glucagon 321 Human growth hormone (hGH) 324 Growth hormone releasing factor (GHRF) and inhibitory factor (GHRIF) 325 The GH receptor 325 Biological effects of GH 327 Therapeutic uses of GH 328 Recombinant hGH (rhGH) and pituitary dwarfism 328 Idiopathic short stature and Turner’s syndrome 330 Metabolic effects of hGH 330 GH, lactation and ovulation 331 The gonadotrophins 331 Follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotrophin (hCG) 331 Pregnant mare serum gonadotrophin (PMSG) 335 The inhibins and activins 337 LHRH and regulation of gonadotrophin production 338 Medical and veterinary applications of gonadotrophins 339 Sources and medical uses of FSH, LHand hCG 340 Recombinant gonadotrophins 342 Veterinary uses of gonadotrophins 344 Gonadotrophin releasing hormone (GnRH) 345 Additional recombinant hormones now approved 345 Conclusions 348 Further reading 348 Chapter 9 Blood products and therapeutic enzymes 351 Disease transmission 351 Whole blood 353 Platelets and red blood cells 353 Blood substitutes 353 Dextrans 354 Albumin 355 Gelatin 357 Oxygen-carrying blood substitutes 357 Haemostasis 358 The coagulation pathway 358 Terminal steps of coagulation pathway 361 Clotting disorders 365 Factor VIII and haemophilia 366 Production of Factor VIII 368 Factors IX, VII a and XIII 371 Anticoagulants 372 Heparin 372 Vitamin Kantimetabolites 375 Hirudin 375 Antithrombin 379 Thrombolytic agents 380 Tissue plasminogen activator (tPA) 381 First-generation tPA 383 Engineered tPA 383 Streptokinase 385 Urokinase 386 Staphylokinase 386 a1 -Antitrypsin 388 Enzymes of therapeutic value 389 Asparaginase 390 DNase 392 Glucocerebrosidase 393 a-Galactosidase and urate oxidase 395 Superoxide dismutase 397 Debriding agents 397 Digestive aids 398 Lactase 400 Further reading 400 Chapter 10 Antibodies, vaccines and adjuvants 403 Polyclonal antibody preparations 403 Anti-D immunoglobulin 406 Normal immunoglobulins 407 Hepatitis Band tetanus immunoglobulin 407 Snake and spider antivenins 408 Monoclonal antibodies 409 Production of monoclonals via hybridoma technology 411 Antibody screening: phage display technology 412 Therapeutic application of monoclonal antibodies 414 Tumour immunology 415 Antibody-based strategies for tumour detection/destruction 417 Drug-based tumour immunotherapy 424 First-generation anti-tumour antibodies: clinical disappointment 426 Tumour-associated antigens 426 Antigenicity of murine monoclonals 428 Chimaeric and humanized antibodies 429 Antibody fragments 432 Additional therapeutic applications of monoclonal antibodies 433 Cardiovascular and related disease 433 Infectious diseases 433 Autoimmune disease 434 Transplantation 434 Vaccine technology 435 Traditional vaccine preparations 436 Attenuated, dead or inactivated bacteria 438 Attenuated and inactivated viral vaccines 439 Toxoids, antigen-based and other vaccine preparations 440 The impact of genetic engineering on vaccine technology 441 Peptide vaccines 444 Vaccine vectors 445 Development of an AIDS vaccine 447 Difficulties associated with vaccine development 450 AIDS vaccines in clinical trials 450 Cancer vaccines 452 Recombinant veterinary vaccines 452 Adjuvant technology 453 Adjuvant mode of action 455 Mineral-based adjuvants 455 Oil-based emulsion adjuvants 455 Bacteria/bacterial products as adjuvants 457 Additional adjuvants 458 Further reading 460 Chapter 11 Nucleic acid therapeutics 463 Gene therapy 463 Basic approach to gene therapy 464 Some additional questions 467 Vectors used in gene therapy 468 Retroviral vectors 468 Additional viral-based vectors 472 Manufacture of viral vectors 474 Non-viral vectors 476 Manufacture of plasmid DNA 480 Gene therapy and genetic disease 482 Gene therapy and cancer 485 Gene therapy and AIDS 486 Gene-based vaccines 488 Gene therapy: some additional considerations 488 Anti-sense technology 488 Anti-sense oligonucleotides 490 Uses, advantages and disadvantages of ‘oligos’ 491 Delivery and cellular uptake of oligonucleotides 493 Manufacture of oligonucleotides 493 Vitravene, an approved antisense agent 494 Antigene sequences and ribozymes 494 Conclusion 495 Further reading 496 Appendix 1 Biopharmaceuticals thus far approved in the USA or European Union 499 Appendix 2 Some Internet addresses relevant to the biopharmaceutical sector 509 Appendix 3 Two selected monographs reproduced from the European Pharmacopoeia with permission from the European Commission: I. Products of recombinant DNA technology 515 II. Interferon a-2 concentrated solution 520 Appendix 4 Manufacture of biological medicinal products for human use. (Annex 2 from The Rules Governing Medicinal Products in the European Community, Vol. 4, Good Manufacturing Practice for Medicinal Products) 527 Index 533

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Book SynopsisSets forth the history, state of the science, and future directions of drug discovery Edited by Jie Jack Li and Nobel laureate E. J. Corey, two leading pioneers in drug discovery and medicinal chemistry, this book synthesizes great moments in history, the current state of the science, and future directions of drug discovery into one expertly written and organized work. Exploring all major therapeutic areas, the book introduces readers to all facets and phases of drug discovery, including target selection, biological testing, drug metabolism, and computer-assisted drug design. Drug Discovery features chapters written by an international team of pharmaceutical and medicinal chemists. Contributions are based on a thorough review of the current literature as well as the authors'' firsthand laboratory experience in drug discovery. The book begins with the history of drug discovery, describing groundbreaking moments in the field. Next, it covers such topics as:Trade Review“Taken together, the book is an excellent introduction into drug discovery and an eminent summary of the very important milestones of drug discovery in the most critical indication areas. This book is a valuable addition to the library of all different kinds of scientists working in the field of drug discovery.” (ChemMedChem, 1 October 2013)Table of ContentsChapter 1. History of Drug Discovery 1 1. Introduction 1 2. Antibacterials 1 3. Cancer Drugs 6 4. Cardiovascular Drugs 10 5. Cholesterol Drugs 16 6. CNS Drugs 21 7. Anti-inflammatory Drugs 26 8. Anti-ulcer Drugs 30 9. Antiviral Drugs 33 10. References 38 Chapter 2. Target Identification and Validation 43 1. History 43 2. Definition of Drug Targets 43 3. Classification of Currently Utilized Drug Targets 45 4. Receptors as Drug Targets 46 5. Enzymes as Drug Targets 48 6. Transporter Proteins as Drug Targets 49 7. Modern Technologies Employed in Target Identification and Validation 49 8. Impact of Therapeutic Modalities on the Selection Drug Targets 62 9. Future Directions 63 10. References 3. In vitro and in vivo Assays 67 1. Introduction 67 2. The Testing Funnel 67 3. In vitro assays 70 4. In vivo Assays 89 5. Outlook 92 6. References 93 Chapter 4. Drug Metabolism and Pharmacokinetics in Drug Discovery 95 1. Introduction 95 2. Drug Metabolism 97 3. Pharmacokinetic Fundamentals 106 4. Drug Metabolism and Pharmacokinetics in Drug Discovery 95 1. Introduction 95 2. Drug Metabolism 97 3. Pharmacokinetic Fundamentals 106 4. Pharmacokinetics Studies in Support of Drug Optimization 112 5. Absorption and Permeability 114 6. Drug Transporters 117 7. Protein Binding 119 8. Pharmacokinetics and Pharmacodynamics 123 9. Predicting Human Pharmacokinetics 130 10. Summary 133 11. References 133 Chapter 5. Cardiovascular Drugs 137 1. Introduction 137 2. Early History of Coronary Heart Disease (CHD) 138 3. Lipid Lowering Agents 139 4. Antihypertensive Agents 153 5. Antithrombotic Drugs 177 6. Thrombolytic Agents 190 7. Anti-anginal Agents 191 8. Heart Failure Drugs 191 9. The Future 193 10. References 193 Chapter 6. Diabetes Drugs 201 1. Introduction 201 2. Current therapies for Type 2 Diabetes 204 3. Other Treatments for T2DM 215 4. Novel Mechanisms of Action: Future Treatments for Type 2 Diabetes 217 5. Current Therapies for Type 1 Diabetes 221 6. Future Treatments for Type 1 Diabetes 227 7. Future Prospects for New Diabetes Drugs 231 8. References 231 Chapter 7. CNS Drugs 241 1. Introduction 241 2. Antipsychotic Drugs 241 3. Antidepressant drugs 246 4. Drugs for Epilepsy and Bipolar Disorder 255 5. Anxiolytic Drugs 259 6. Centrally Acting Analgesic Drugs 262 7. Drugs for treating Substance Abuse and ADHD 265 8. Drugs for Neurodegenerative Diseases 267 9. Future Prospects for New CNS Drugs 273 10. References 276 Chapter 8. Cancer Drugs 283 1. Introduction 283 2. Historical Perspective of Cancer Drugs 285 3. Antimetabolites 286 4. Alkylating Agents 291 5. Platinum Complexes 294 6. Plant and Marine Based Natural Products 295 7. Toposiomerase Inhibitors 300 8. Antitumor Antibiotics 305 9. Tyrosine Kinase Inhibitors (TKI) 306 10. Hormones 314 11. Histone Deacylase (HDAC) Inhibitors 321 12. Miscellaneous Cancer Drugs 323 13. Conclusion 325 14. References 326 Chapter 9. Antiinflammatory and Immunomodulatory Drugs 333 1. Introduction 333 2. Arachidonic Acid Cascade 334 3. Leukotriene Pathway Inhibitors 347 4. Anti-histamines 351 5. Corticosteroids 353 6. Rheumatoid Arthritis 356 7. Osteoarthritis 363 8. Chronic Inflammatory Arthritis and Gout 364 9. Multiple Sclerosis 366 10. Transplantation 368 11. Biological Agents That Suppress Cytokine Production or Signaling 372 12. B Cell Therapy 374 13. Cytotoxic T-lymphocyte Antigen 4 (CTLA4) 374 14. Interleukins 375 15. Safety 377 16. Summary 377 17. References 378 Chapter 10. Anti-bacterial Drugs 385 1. Introduction 385 2. The Rise and Decline of Antibiotics 386 3. The Unique Challenges of Anti-bacterial Drug Discovery 387 4. Antibiotic Classes 390 5. Emerging Strategies to Discover New Anti-bacterial Drugs 420 6. Conclusions 425 7. References 425 Chapter 11. Antiviral Drug Discovery 437 1. Introduction 437 2. Human Immunodeficiency Virus-1 Inhibitors 442 3. Hepatitis B Virus Inhibitors 459 4. Hepatitis C Virus Inhibitors 463 5. Inhibitors of Respiratory Viruses-Influenza and Respiratory Syncytial Virus 476 6. Herpesviridae Inhibitors 487 7. Epilogue 490 8. References 490 Index 517

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