{"product_id":"antitargets-and-drug-safety-9783527335114","title":"Antitargets and Drug Safety","description":"\u003cb\u003eBook Synopsis\u003c\/b\u003e\u003cbr\u003eWith its focus on emerging concerns of kinase and GPCR-mediated antitarget effects, this vital reference for drug developers addresses one of the hot topics in drug safety now and in future.\u003cbr\u003e Divided into three major parts, the first section deals with novel technologies and includes the utility of adverse event reports to drug discovery, the translational aspects of preclinical safety findings, broader computational prediction of drug side-effects, and a description of the serotonergic system. The main part of the book looks at some of the most common antitarget-mediated side effects, focusing on hepatotoxicity in drug safety, cardiovascular toxicity and signaling effects via kinase and GPCR anti-targets. In the final section, several case studies of recently developed drugs illustrate how to prevent anti-target effects and how big pharma deals with them if they occur. The more recent field of systems pharmacology has gained prominence and this is reflected in chapters dedicated to the utility in deciphering and modeling anti-targets. The final chapter is concerned with those compounds that inadvertently elicit CNS mediated adverse events, including a pragmatic description of ways to mitigate these types of safety risks.\u003cbr\u003e Written as a companion to the successful book on antitargets by Vaz and Klabunde, this new volume focuses on recent progress and new classes, methods and case studies that were not previously covered.\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTrade Review\u003c\/b\u003e\u003cbr\u003e\u003cp\u003e“Overall, there is plenty of information in this book making it a valuable indepth reading matter for experts working in the complex and quickly evolving scientific field of translational safety.  Academic students and new industrial recruits will also profit from selected chapters of this reference book.”  (\u003ci\u003eChemMedChem\u003c\/i\u003e\u003ci\u003e, 1 October 20\u003c\/i\u003e15)\u003c\/p\u003e \u003cp\u003e \u003c\/p\u003e\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTable of Contents\u003c\/b\u003e\u003cbr\u003e\u003cp\u003eList of Contributors XV\u003c\/p\u003e \u003cp\u003ePreface XXI\u003c\/p\u003e \u003cp\u003eA Personal Foreword XXIII\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection 1 General Concept for Target-based Safety Assessment 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance 3\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eSteven Whitebread, Mateusz Maciejewski, Alexander Fekete, Eugen Lounkine, and László Urbán\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Introduction 3\u003c\/p\u003e \u003cp\u003e1.2 Postmarketing Pharmacovigilance 6\u003c\/p\u003e \u003cp\u003e1.3 Polypharmacy and Pharmacological Promiscuity of Marketed Drugs 9\u003c\/p\u003e \u003cp\u003eReferences 15\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 In Silico Prediction of Drug Side Effects 19\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eMichael J. Keiser\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Large-Scale Prediction of Drug Activity 20\u003c\/p\u003e \u003cp\u003e2.1.1 Networks of Known and New Target Activity 21\u003c\/p\u003e \u003cp\u003e2.1.2 Resources for Multiscale Inquiry 25\u003c\/p\u003e \u003cp\u003e2.2 Multiscale Models of Adverse Drug Reactions 30\u003c\/p\u003e \u003cp\u003e2.2.1 Inferring Adverse Reactions 31\u003c\/p\u003e \u003cp\u003e2.2.2 Forward Perturbation and Prediction of Mechanisms 33\u003c\/p\u003e \u003cp\u003eReferences 36\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Translational Value of Preclinical Safety Assessment: System Organ Class (SOC) Representation of Off-Targets 45\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eMateusz Maciejewski, Eugen Lounkine, Andreas Hartmann, Steven Whitebread, and László Urbán\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction 45\u003c\/p\u003e \u003cp\u003e3.2 Terminology: Medicinal Dictionary for Regulatory Activities (MedDRA) 46\u003c\/p\u003e \u003cp\u003e3.2.1 Correct Use of MedDRA Terminology at Different Phases of Drug Discovery 48\u003c\/p\u003e \u003cp\u003e3.2.2 Determination of Symptoms Associated with a Target 50\u003c\/p\u003e \u003cp\u003e3.3 Data Interpretation: Modifying Factors 52\u003c\/p\u003e \u003cp\u003e3.3.1 Access to Organs 52\u003c\/p\u003e \u003cp\u003e3.3.2 Off-Target Promiscuity: Target Interactions (Synergies and Antagonism) 53\u003c\/p\u003e \u003cp\u003e3.4 Conclusions 53\u003c\/p\u003e \u003cp\u003eReferences 54\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Pathological Conditions Associated with the Disturbance of the 5-HT System 57\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eDaniel Hoyer\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 57\u003c\/p\u003e \u003cp\u003e4.2 From “St. Anthony’s Fire” to Ergot Alkaloids, the Serotonin Syndrome, and Modern 5-HT Pharmacology 59\u003c\/p\u003e \u003cp\u003e4.3 Appetite-Reducing Agents, Fenfluramine, and Other 5-HT Releasers 61\u003c\/p\u003e \u003cp\u003e4.4 Gastrointestinal and Antiemetic Indications, the 5-HT3\/5-HT4 Receptor Links 63\u003c\/p\u003e \u003cp\u003e4.5 Antipsychotics and the 5-HT2\/Dopamine D2 Link (and Many Other 5-HT Receptors) 65\u003c\/p\u003e \u003cp\u003e4.6 Antimigraine Medications of Old and New and the 5-HT1B\/1D Receptors 67\u003c\/p\u003e \u003cp\u003e4.7 Antidepressants\/Anxiolytics Acting at 5-HT and Other Transporters 69\u003c\/p\u003e \u003cp\u003e4.8 Conclusions 71\u003c\/p\u003e \u003cp\u003eReferences 72\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection 2 Hepatic Side Effects 81\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Drug-Induced Liver Injury: Clinical and Diagnostic Aspects 83\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eJohn R. Senior\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 83\u003c\/p\u003e \u003cp\u003e5.1.1 Postmarketing Hepatotoxicity versus Hepatotoxicity in Development 84\u003c\/p\u003e \u003cp\u003e5.1.2 Isoniazid – If It Were Newly Discovered, Would It Be Approved Today? 85\u003c\/p\u003e \u003cp\u003e5.2 Special Problems of Postmarketing Hepatotoxicity 89\u003c\/p\u003e \u003cp\u003e5.2.1 Voluntary Monitoring after Approval for Marketing 90\u003c\/p\u003e \u003cp\u003e5.2.2 Prediction of Serious, Dysfunctional Liver Injury 90\u003c\/p\u003e \u003cp\u003e5.2.3 Severity of Liver Injury Is Not Measured by Aminotransferase Elevations 91\u003c\/p\u003e \u003cp\u003e5.2.4 Attempts to Standardize Terminology 91\u003c\/p\u003e \u003cp\u003e5.2.5 What Is the “Normal” Range, or the “Upper Limit of Normal”? 92\u003c\/p\u003e \u003cp\u003e5.2.6 Diagnostic Test Evaluation 93\u003c\/p\u003e \u003cp\u003e5.2.7 Determination of the Likely Cause of Liver Abnormalities 94\u003c\/p\u003e \u003cp\u003e5.2.8 Treatment and Management of DILI in Practice 95\u003c\/p\u003e \u003cp\u003e5.3 Special Problems for New Drug Development 95\u003c\/p\u003e \u003cp\u003e5.3.1 How Many? 95\u003c\/p\u003e \u003cp\u003e5.3.2 How Much? 96\u003c\/p\u003e \u003cp\u003e5.3.3 How Soon? 97\u003c\/p\u003e \u003cp\u003e5.3.4 How Likely? 97\u003c\/p\u003e \u003cp\u003e5.3.5 Compared with What? 97\u003c\/p\u003e \u003cp\u003e5.3.6 ROC Curves 98\u003c\/p\u003e \u003cp\u003e5.3.7 eDISH: Especially for Controlled Trials 99\u003c\/p\u003e \u003cp\u003e5.3.8 Test Validation and Qualification 100\u003c\/p\u003e \u003cp\u003e5.4 Closing Considerations 101\u003c\/p\u003e \u003cp\u003e5.4.1 A Handful of “Do Nots” 101\u003c\/p\u003e \u003cp\u003e5.4.2 Need to Standardize ALT Measurement and Interpretation of Normal Ranges 102\u003c\/p\u003e \u003cp\u003e5.4.3 Research Opportunities 102\u003c\/p\u003e \u003cp\u003eReferences 103\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Mechanistic Safety Biomarkers for Drug-Induced Liver Injury 107\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eDaniel J. Antoine\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 107\u003c\/p\u003e \u003cp\u003e6.2 Drug-Induced Toxicity and the Liver 110\u003c\/p\u003e \u003cp\u003e6.3 Current Status of Biomarkers for the Assessment of DILI 111\u003c\/p\u003e \u003cp\u003e6.4 Novel Investigational Biomarkers for DILI 113\u003c\/p\u003e \u003cp\u003e6.4.1 Glutamate Dehydrogenase (GLDH) 114\u003c\/p\u003e \u003cp\u003e6.4.2 Acylcarnitines 115\u003c\/p\u003e \u003cp\u003e6.4.3 High-Mobility Group Box-1 (HMGB1) 116\u003c\/p\u003e \u003cp\u003e6.4.4 Keratin 18 (K18) 116\u003c\/p\u003e \u003cp\u003e6.4.5 MicroRNA-122 (miR-122) 117\u003c\/p\u003e \u003cp\u003e6.5 Conclusions and Future Perspectives 118\u003c\/p\u003e \u003cp\u003eReferences 120\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 In Vitro Models for the Prediction of Drug-Induced Liver Injury in Lead Discovery 125\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eFrederic Moulin and Oliver Flint\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 125\u003c\/p\u003e \u003cp\u003e7.2 Simple Systems for the Detection and Investigation of Hepatic Toxicants 130\u003c\/p\u003e \u003cp\u003e7.2.1 Primary Hepatocytes 130\u003c\/p\u003e \u003cp\u003e7.2.2 Liver-Derived Cell Lines 135\u003c\/p\u003e \u003cp\u003e7.2.3 Differentiated Pluripotent Stem Cells 137\u003c\/p\u003e \u003cp\u003e7.3 Models to Mitigate Hepatocyte Dedifferentiation 140\u003c\/p\u003e \u003cp\u003e7.3.1 Liver Slices 140\u003c\/p\u003e \u003cp\u003e7.3.2 Selective Engineering of Metabolism 141\u003c\/p\u003e \u003cp\u003e7.4 Understanding Immune-Mediated Hepatotoxicity 144\u003c\/p\u003e \u003cp\u003e7.4.1 Use of Inflammatory Cofactors 145\u003c\/p\u003e \u003cp\u003e7.4.2 Innate Immune System and Inflammasome 147\u003c\/p\u003e \u003cp\u003e7.5 Conclusions 148\u003c\/p\u003e \u003cp\u003eReferences 149\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Transporters in the Liver 159\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eBruno Stieger and Gerd A. Kullak-Ublick\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 159\u003c\/p\u003e \u003cp\u003e8.2 Role of Organic Anion Transporters for Drug Uptake 159\u003c\/p\u003e \u003cp\u003e8.3 Drug Interaction with the Bile Salt Export Pump 160\u003c\/p\u003e \u003cp\u003e8.4 Susceptibility Factors for Drug–BSEP Interactions 161\u003c\/p\u003e \u003cp\u003e8.5 Role of BSEP in Drug Development 162\u003c\/p\u003e \u003cp\u003eReferences 163\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Mechanistic Modeling of Drug-Induced Liver Injury (DILI) 173\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eKyunghee Yang, Jeffrey L. Woodhead, Lisl K. Shoda, Yuching Yang, Paul B. Watkins, Kim L.R. Brouwer, Brett A. Howell, and Scott Q. Siler\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 173\u003c\/p\u003e \u003cp\u003e9.2 Mechanistic Modules in DILIsymðD version 3A 175\u003c\/p\u003e \u003cp\u003e9.2.1 Oxidative Stress-Mediated Toxicity 175\u003c\/p\u003e \u003cp\u003e9.2.2 Innate Immune Responses 178\u003c\/p\u003e \u003cp\u003e9.2.3 Mitochondrial Toxicity 179\u003c\/p\u003e \u003cp\u003e9.2.4 Bile Acid-Mediated Toxicity 181\u003c\/p\u003e \u003cp\u003e9.3 Examples of Bile Acid-Mediated Toxicity Module 184\u003c\/p\u003e \u003cp\u003e9.3.1 Troglitazone and Pioglitazone 184\u003c\/p\u003e \u003cp\u003e9.3.2 Bosentan and Telmisartan 187\u003c\/p\u003e \u003cp\u003e9.4 Conclusions and Future Directions 190\u003c\/p\u003e \u003cp\u003eReferences 191\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection 3 Cardiovascular Side Effects 199\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Functional Cardiac Safety Evaluation of Novel Therapeutics 201\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eJean-Pierre Valentin, Brian Guth, Robert L. Hamlin, Pierre Lainée, Dusty Sarazan, and Matt Skinner\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction: What Is the Issue? 201\u003c\/p\u003e \u003cp\u003e10.2 Cardiac Function: Definitions and General Principles 203\u003c\/p\u003e \u003cp\u003e10.2.1 Definition and Importance of Inotropy and Difference from Ventricular Function 203\u003c\/p\u003e \u003cp\u003e10.2.2 Definition and Importance of Lusitropy 207\u003c\/p\u003e \u003cp\u003e10.2.3 Components and Importance of the Systemic Arterial Pressure 211\u003c\/p\u003e \u003cp\u003e10.3 Methods Available to Assess Cardiac Function 213\u003c\/p\u003e \u003cp\u003e10.4 What Do We Know About the Translation of the Nonclinical Findings to Humans? 217\u003c\/p\u003e \u003cp\u003e10.5 Risk Assessment 219\u003c\/p\u003e \u003cp\u003e10.5.1 Hazard Identification 219\u003c\/p\u003e \u003cp\u003e10.5.2 Risk Assessment 221\u003c\/p\u003e \u003cp\u003e10.5.3 Risk Management 224\u003c\/p\u003e \u003cp\u003e10.5.4 Risk Mitigation 225\u003c\/p\u003e \u003cp\u003e10.6 Summary, Recommendations, and Conclusions 227\u003c\/p\u003e \u003cp\u003eReferences 228\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Safety Aspects of the Cav1.2 Channel 235\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eBerengere Dumotier and Martin Traebert\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 235\u003c\/p\u003e \u003cp\u003e11.2 Structure of Cav1.2 Channels 235\u003c\/p\u003e \u003cp\u003e11.2.1 α-Subunit of Cav1.2 Channel 236\u003c\/p\u003e \u003cp\u003e11.2.2 β-Subunit of Cav1.2 Channel 236\u003c\/p\u003e \u003cp\u003e11.3 Function of Cav1.2 Channels in Cardiac Tissue 237\u003c\/p\u003e \u003cp\u003e11.3.1 Role in Conduction and Contractility 239\u003c\/p\u003e \u003cp\u003e11.3.2 Modulation of Cav1.2 Channels 240\u003c\/p\u003e \u003cp\u003e11.3.3 Cav1.2 and Cardiac Diseases 244\u003c\/p\u003e \u003cp\u003e11.4 Pharmacology of Cav1.2 Channels: Translation to the Clinic 245\u003c\/p\u003e \u003cp\u003e11.4.1 Cav1.2 Antagonists: Impact on Electromechanical Functions 245\u003c\/p\u003e \u003cp\u003e11.5 Prediction of Cav1.2 Off-Target Liability 246\u003c\/p\u003e \u003cp\u003e11.5.1 Cav1.2 in Cardiomyocytes Derived from iPS Cells 246\u003c\/p\u003e \u003cp\u003eReferences 247\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Cardiac Sodium Current (Nav1.5) 253\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eGary Gintant\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Background and Scope 253\u003c\/p\u003e \u003cp\u003e12.2 Structure and Function 255\u003c\/p\u003e \u003cp\u003e12.2.1 Molecular Biology 255\u003c\/p\u003e \u003cp\u003e12.2.2 SCN5A Mutations Related to Congenital Long QT Syndromes 256\u003c\/p\u003e \u003cp\u003e12.2.3 Evidence for Multiple Functional Types of Cardiac Sodium Channels and Heterogeneous Distribution 257\u003c\/p\u003e \u003cp\u003e12.3 Physiological Role and Drug Actions 258\u003c\/p\u003e \u003cp\u003e12.3.1 Fast Sodium Current (INaF): Conduction and Refractoriness 258\u003c\/p\u003e \u003cp\u003e12.3.2 Late (or Residual or Slow) Sodium Current (INaL) 259\u003c\/p\u003e \u003cp\u003e12.3.3 Drug Effects on INaF 261\u003c\/p\u003e \u003cp\u003e12.3.4 Indirect Modulation of INaF 264\u003c\/p\u003e \u003cp\u003e12.4 Methodology 265\u003c\/p\u003e \u003cp\u003e12.4.1 Use of Human Stem Cell-Derived Cardiomyocytes 266\u003c\/p\u003e \u003cp\u003e12.5 Translation of Effects on INaF: Relation to Conduction Velocity and Proarrhythmia 268\u003c\/p\u003e \u003cp\u003e12.6 Conclusions 269\u003c\/p\u003e \u003cp\u003eReferences 270\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Circulating Biomarkers for Drug-Induced Cardiotoxicity: Reverse Translation from Patients to Nonclinical Species 279\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eGül Erdemli, Haisong Ju, and Sarita Pereira\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 279\u003c\/p\u003e \u003cp\u003e13.2 Cardiac Troponins 280\u003c\/p\u003e \u003cp\u003e13.3 Natriuretic Peptides 282\u003c\/p\u003e \u003cp\u003e13.4 Novel\/Exploratory Biomarkers: H-FABP, miRNA, and Genomic Biomarkers 285\u003c\/p\u003e \u003cp\u003e13.5 Regulatory Perspective 286\u003c\/p\u003e \u003cp\u003e13.6 Conclusions and Future Perspectives 288\u003c\/p\u003e \u003cp\u003eReferences 289\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 The Mechanistic Basis of hERG Blockade and the Proarrhythmic Effects Thereof 295\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eRobert A. Pearlstein, K. Andrew MacCannell, Qi-Ying Hu, Ramy Farid, and José S. Duca\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 295\u003c\/p\u003e \u003cp\u003e14.1.1 The Role of hERG Dysfunction\/Blockade in Promoting Early After Depolarizations 296\u003c\/p\u003e \u003cp\u003e14.1.2 The Dynamics of hERG Blockade 301\u003c\/p\u003e \u003cp\u003e14.1.3 Simulations of the Human Cardiac AP in the Presence of hERG Blockade 303\u003c\/p\u003e \u003cp\u003e14.1.4 Estimation of Proarrhythmic hERG Occupancy Levels Based on AP Simulations 304\u003c\/p\u003e \u003cp\u003e14.1.5 Novel Insights about the Causes of Inadvertent hERG Binding Function 305\u003c\/p\u003e \u003cp\u003e14.1.6 Implications of Our Findings for hERG Safety Assessment 313\u003c\/p\u003e \u003cp\u003e14.1.7 Conclusion and Future Directions 324\u003c\/p\u003e \u003cp\u003eReferences 324\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection 4 Kinase Antitargets 329\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Introduction to Kinase Antitargets 331\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eMark C. Munson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eReferences 360\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Clinical and Nonclinical Adverse Effects of Kinase Inhibitors 365\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eDouglas A. Keller, Richard J. Brennan, and Karen L. Leach\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 365\u003c\/p\u003e \u003cp\u003e16.2 Perspectives on the Clinical Safety of Kinase Inhibitor Therapy 371\u003c\/p\u003e \u003cp\u003e16.3 Adverse Effects of Kinase Inhibitor Drugs 372\u003c\/p\u003e \u003cp\u003e16.3.1 Hepatic Toxicity 372\u003c\/p\u003e \u003cp\u003e16.3.2 Thyroid Toxicity 377\u003c\/p\u003e \u003cp\u003e16.3.3 Bone and Tooth Toxicity 379\u003c\/p\u003e \u003cp\u003e16.3.4 Cardiovascular Toxicity 380\u003c\/p\u003e \u003cp\u003e16.3.5 Cutaneous Toxicity 380\u003c\/p\u003e \u003cp\u003e16.3.6 Developmental and Reproductive Toxicity 383\u003c\/p\u003e \u003cp\u003e16.3.7 Gastrointestinal Toxicity 385\u003c\/p\u003e \u003cp\u003e16.3.8 Hematopoietic Toxicity 385\u003c\/p\u003e \u003cp\u003e16.3.9 Ocular Toxicity 387\u003c\/p\u003e \u003cp\u003e16.3.10 Pulmonary Toxicity 388\u003c\/p\u003e \u003cp\u003e16.3.11 Renal Toxicity 389\u003c\/p\u003e \u003cp\u003e16.4 Derisking Strategies for Kinase Inhibitor Toxicity 389\u003c\/p\u003e \u003cp\u003e16.5 Concluding Remarks 391\u003c\/p\u003e \u003cp\u003eReferences 391\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Cardiac Side Effects Associated with Kinase Proteins and Their Signaling Pathways 401\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eRoy J. Vaz and Vinod F. Patel\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 A Case Study 401\u003c\/p\u003e \u003cp\u003e17.2 Introduction 402\u003c\/p\u003e \u003cp\u003e17.3 Cardiac-Specific Kinase Antitargets 404\u003c\/p\u003e \u003cp\u003e17.3.1 Preclinical Findings in Genetically Modified or KI-Treated Mice 404\u003c\/p\u003e \u003cp\u003e17.3.2 Clinical Findings of Kinase Inhibitors on the Heart and Their Mechanistic Understandings 404\u003c\/p\u003e \u003cp\u003e17.4 Current and Future Directions 409\u003c\/p\u003e \u003cp\u003e17.4.1 Preclinical Safety and Clinical Outcome Predictions 409\u003c\/p\u003e \u003cp\u003e17.5 Conclusions 410\u003c\/p\u003e \u003cp\u003eReferences 411\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Case Studies: Selective Inhibitors of Protein Kinases – Exploiting Demure Features 413\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eEllen R. Laird\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 413\u003c\/p\u003e \u003cp\u003e18.2 Case I: Indane Oximes as Selective B-Raf Inhibitors 414\u003c\/p\u003e \u003cp\u003e18.3 Case II: ARRY-380 (ONT-380) – an ErbB2 Agent that Spares EGFR 420\u003c\/p\u003e \u003cp\u003e18.4 Case III: Discovery of GDC-0068 (Ipatasertib), a Potent and Selective ATP-Competitive Inhibitor of AKT 424\u003c\/p\u003e \u003cp\u003e18.5 Concluding Remarks 428\u003c\/p\u003e \u003cp\u003eReferences 429\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSection 5 Examples of Clinical Translation 435\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 Torcetrapib and Dalcetrapib Safety: Relevance of Preclinical In Vitro and In Vivo Models 437\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eEric J. Niesor, Andrea Greiter-Wilke, and Lutz Müller\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 437\u003c\/p\u003e \u003cp\u003e19.2 Effect of Torcetrapib on Blood Pressure 437\u003c\/p\u003e \u003cp\u003e19.3 In Vitro Studies 438\u003c\/p\u003e \u003cp\u003e19.3.1 Direct Effect of Torcetrapib on Aldosterone Production In Vitro in Cultured H295R Adrenal Corticocarcinoma Cells 439\u003c\/p\u003e \u003cp\u003e19.3.2 Molecular Mechanism of Torcetrapib Induction of Aldosterone Secretion 439\u003c\/p\u003e \u003cp\u003e19.3.3 Development of Reproducible In Vitro Screening Models for Increase in Aldosterone and Cyp11B2 mRNA in a Human Adrenal Corticocarcinoma Cell Line 440\u003c\/p\u003e \u003cp\u003e19.3.4 Application of In Vitro Models for the Successful Derisking of Dalcetrapib, Anacetrapib, and Evacetrapib 440\u003c\/p\u003e \u003cp\u003e19.4 In Vivo Studies 441\u003c\/p\u003e \u003cp\u003e19.4.1 Effect of Torcetrapib on Aldosterone and BP 441\u003c\/p\u003e \u003cp\u003e19.4.2 Molecular Mechanisms of Torcetrapib-Induced BP Increase 444\u003c\/p\u003e \u003cp\u003e19.5 General Safety Risk with Increased Aldosterone and BP 447\u003c\/p\u003e \u003cp\u003e19.5.1 Inappropriate Increase in Aldosterone Secretion May Increase CV Risks 447\u003c\/p\u003e \u003cp\u003e19.6 Relevance of BP and Aldosterone Preclinical Models to Clinical Observation with Dalcetrapib and Anacetrapib 448\u003c\/p\u003e \u003cp\u003e19.7 Similarities between Potent CETPi and Halogenated Hydrocarbons 449\u003c\/p\u003e \u003cp\u003e19.7.1 The Macrophage Scavenger Receptor MARCO, a Possible Antitarget for Dalcetrapib, and Its Relevance to Humans 450\u003c\/p\u003e \u003cp\u003e19.8 Conclusions 451\u003c\/p\u003e \u003cp\u003eReferences 451\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Targets Associated with Drug-Related Suicidal Ideation and Behavior 457\u003c\/b\u003e\u003cbr\u003e\u003ci\u003eAndreas Hartmann, Steven Whitebread, Jacques Hamon, Alexander Fekete, Christian Trendelenburg, Patrick Y. Müller, and László Urbán\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 457\u003c\/p\u003e \u003cp\u003e20.2 Targets Associated with Increased Suicidal Intent and Behavior 458\u003c\/p\u003e \u003cp\u003e20.2.1 G-Protein-Coupled Receptors 458\u003c\/p\u003e \u003cp\u003e20.2.2 Transporters 466\u003c\/p\u003e \u003cp\u003e20.2.3 Ion Channels 469\u003c\/p\u003e \u003cp\u003e20.3 Conclusions 472\u003c\/p\u003e \u003cp\u003eReferences 473\u003c\/p\u003e \u003cp\u003eIndex 479\u003c\/p\u003e","brand":"Wiley-VCH Verlag GmbH","offers":[{"title":"Default Title","offer_id":53196948144471,"sku":"9783527335114","price":128.66,"currency_code":"GBP","in_stock":false}],"url":"https:\/\/bookcurl.com\/products\/antitargets-and-drug-safety-9783527335114","provider":"Book Curl","version":"1.0","type":"link"}