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Antitargets and Drug Safety

Methods & Principles in Medicinal Chemistry, Band 66 1. Aufl.

von: Laszlo Urban, Vinod Patel, Roy J. Vaz
151,99 €
Verlag:	Wiley-VCH
Format:	EPUB
Veröffentl.:	23.02.2015
ISBN/EAN:	9783527673667
Sprache:	englisch
Anzahl Seiten:	528

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Beschreibungen

Titelbeschreibung

With 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. 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. 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.

Inhaltsverzeichnis

List of Contributors XV Preface XXI A Personal Foreword XXIII Section 1 General Concept for Target-based Safety Assessment 1 1 Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance 3 Steven Whitebread, Mateusz Maciejewski, Alexander Fekete, Eugen Lounkine, and László Urbán 1.1 Introduction 3 1.2 Postmarketing Pharmacovigilance 6 1.3 Polypharmacy and Pharmacological Promiscuity of Marketed Drugs 9 References 15 2 In Silico Prediction of Drug Side Effects 19 Michael J. Keiser 2.1 Large-Scale Prediction of Drug Activity 20 2.1.1 Networks of Known and New Target Activity 21 2.1.2 Resources for Multiscale Inquiry 25 2.2 Multiscale Models of Adverse Drug Reactions 30 2.2.1 Inferring Adverse Reactions 31 2.2.2 Forward Perturbation and Prediction of Mechanisms 33 References 36 3 Translational Value of Preclinical Safety Assessment: System Organ Class (SOC) Representation of Off-Targets 45 Mateusz Maciejewski, Eugen Lounkine, Andreas Hartmann, Steven Whitebread, and László Urbán 3.1 Introduction 45 3.2 Terminology: Medicinal Dictionary for Regulatory Activities (MedDRA) 46 3.2.1 Correct Use of MedDRA Terminology at Different Phases of Drug Discovery 48 3.2.2 Determination of Symptoms Associated with a Target 50 3.3 Data Interpretation: Modifying Factors 52 3.3.1 Access to Organs 52 3.3.2 Off-Target Promiscuity: Target Interactions (Synergies and Antagonism) 53 3.4 Conclusions 53 References 54 4 Pathological Conditions Associated with the Disturbance of the 5-HT System 57 Daniel Hoyer 4.1 Introduction 57 4.2 From “St. Anthony’s Fire” to Ergot Alkaloids, the Serotonin Syndrome, and Modern 5-HT Pharmacology 59 4.3 Appetite-Reducing Agents, Fenfluramine, and Other 5-HT Releasers 61 4.4 Gastrointestinal and Antiemetic Indications, the 5-HT3/5-HT4 Receptor Links 63 4.5 Antipsychotics and the 5-HT2/Dopamine D2 Link (and Many Other 5-HT Receptors) 65 4.6 Antimigraine Medications of Old and New and the 5-HT1B/1D Receptors 67 4.7 Antidepressants/Anxiolytics Acting at 5-HT and Other Transporters 69 4.8 Conclusions 71 References 72 Section 2 Hepatic Side Effects 81 5 Drug-Induced Liver Injury: Clinical and Diagnostic Aspects 83 John R. Senior 5.1 Introduction 83 5.1.1 Postmarketing Hepatotoxicity versus Hepatotoxicity in Development 84 5.1.2 Isoniazid – If It Were Newly Discovered, Would It Be Approved Today? 85 5.2 Special Problems of Postmarketing Hepatotoxicity 89 5.2.1 Voluntary Monitoring after Approval for Marketing 90 5.2.2 Prediction of Serious, Dysfunctional Liver Injury 90 5.2.3 Severity of Liver Injury Is Not Measured by Aminotransferase Elevations 91 5.2.4 Attempts to Standardize Terminology 91 5.2.5 What Is the “Normal” Range, or the “Upper Limit of Normal”? 92 5.2.6 Diagnostic Test Evaluation 93 5.2.7 Determination of the Likely Cause of Liver Abnormalities 94 5.2.8 Treatment and Management of DILI in Practice 95 5.3 Special Problems for New Drug Development 95 5.3.1 How Many? 95 5.3.2 How Much? 96 5.3.3 How Soon? 97 5.3.4 How Likely? 97 5.3.5 Compared with What? 97 5.3.6 ROC Curves 98 5.3.7 eDISH: Especially for Controlled Trials 99 5.3.8 Test Validation and Qualification 100 5.4 Closing Considerations 101 5.4.1 A Handful of “Do Nots” 101 5.4.2 Need to Standardize ALT Measurement and Interpretation of Normal Ranges 102 5.4.3 Research Opportunities 102 References 103 6 Mechanistic Safety Biomarkers for Drug-Induced Liver Injury 107 Daniel J. Antoine 6.1 Introduction 107 6.2 Drug-Induced Toxicity and the Liver 110 6.3 Current Status of Biomarkers for the Assessment of DILI 111 6.4 Novel Investigational Biomarkers for DILI 113 6.4.1 Glutamate Dehydrogenase (GLDH) 114 6.4.2 Acylcarnitines 115 6.4.3 High-Mobility Group Box-1 (HMGB1) 116 6.4.4 Keratin 18 (K18) 116 6.4.5 MicroRNA-122 (miR-122) 117 6.5 Conclusions and Future Perspectives 118 References 120 7 In Vitro Models for the Prediction of Drug-Induced Liver Injury in Lead Discovery 125 Frederic Moulin and Oliver Flint 7.1 Introduction 125 7.2 Simple Systems for the Detection and Investigation of Hepatic Toxicants 130 7.2.1 Primary Hepatocytes 130 7.2.2 Liver-Derived Cell Lines 135 7.2.3 Differentiated Pluripotent Stem Cells 137 7.3 Models to Mitigate Hepatocyte Dedifferentiation 140 7.3.1 Liver Slices 140 7.3.2 Selective Engineering of Metabolism 141 7.4 Understanding Immune-Mediated Hepatotoxicity 144 7.4.1 Use of Inflammatory Cofactors 145 7.4.2 Innate Immune System and Inflammasome 147 7.5 Conclusions 148 References 149 8 Transporters in the Liver 159 Bruno Stieger and Gerd A. Kullak-Ublick 8.1 Introduction 159 8.2 Role of Organic Anion Transporters for Drug Uptake 159 8.3 Drug Interaction with the Bile Salt Export Pump 160 8.4 Susceptibility Factors for Drug–BSEP Interactions 161 8.5 Role of BSEP in Drug Development 162 References 163 9 Mechanistic Modeling of Drug-Induced Liver Injury (DILI) 173 Kyunghee Yang, Jeffrey L. Woodhead, Lisl K. Shoda, Yuching Yang, Paul B. Watkins, Kim L.R. Brouwer, Brett A. Howell, and Scott Q. Siler 9.1 Introduction 173 9.2 Mechanistic Modules in DILIsym?D version 3A 175 9.2.1 Oxidative Stress-Mediated Toxicity 175 9.2.2 Innate Immune Responses 178 9.2.3 Mitochondrial Toxicity 179 9.2.4 Bile Acid-Mediated Toxicity 181 9.3 Examples of Bile Acid-Mediated Toxicity Module 184 9.3.1 Troglitazone and Pioglitazone 184 9.3.2 Bosentan and Telmisartan 187 9.4 Conclusions and Future Directions 190 References 191 Section 3 Cardiovascular Side Effects 199 10 Functional Cardiac Safety Evaluation of Novel Therapeutics 201 Jean-Pierre Valentin, Brian Guth, Robert L. Hamlin, Pierre Lainée, Dusty Sarazan, and Matt Skinner 10.1 Introduction: What Is the Issue? 201 10.2 Cardiac Function: Definitions and General Principles 203 10.2.1 Definition and Importance of Inotropy and Difference from Ventricular Function 203 10.2.2 Definition and Importance of Lusitropy 207 10.2.3 Components and Importance of the Systemic Arterial Pressure 211 10.3 Methods Available to Assess Cardiac Function 213 10.4 What Do We Know About the Translation of the Nonclinical Findings to Humans? 217 10.5 Risk Assessment 219 10.5.1 Hazard Identification 219 10.5.2 Risk Assessment 221 10.5.3 Risk Management 224 10.5.4 Risk Mitigation 225 10.6 Summary, Recommendations, and Conclusions 227 References 228 11 Safety Aspects of the Cav1.2 Channel 235 Berengere Dumotier and Martin Traebert 11.1 Introduction 235 11.2 Structure of Cav1.2 Channels 235 11.2.1 α-Subunit of Cav1.2 Channel 236 11.2.2 β-Subunit of Cav1.2 Channel 236 11.3 Function of Cav1.2 Channels in Cardiac Tissue 237 11.3.1 Role in Conduction and Contractility 239 11.3.2 Modulation of Cav1.2 Channels 240 11.3.3 Cav1.2 and Cardiac Diseases 244 11.4 Pharmacology of Cav1.2 Channels: Translation to the Clinic 245 11.4.1 Cav1.2 Antagonists: Impact on Electromechanical Functions 245 11.5 Prediction of Cav1.2 Off-Target Liability 246 11.5.1 Cav1.2 in Cardiomyocytes Derived from iPS Cells 246 References 247 12 Cardiac Sodium Current (Nav1.5) 253 Gary Gintant 12.1 Background and Scope 253 12.2 Structure and Function 255 12.2.1 Molecular Biology 255 12.2.2 SCN5A Mutations Related to Congenital Long QT Syndromes 256 12.2.3 Evidence for Multiple Functional Types of Cardiac Sodium Channels and Heterogeneous Distribution 257 12.3 Physiological Role and Drug Actions 258 12.3.1 Fast Sodium Current (INaF): Conduction and Refractoriness 258 12.3.2 Late (or Residual or Slow) Sodium Current (INaL) 259 12.3.3 Drug Effects on INaF 261 12.3.4 Indirect Modulation of INaF 264 12.4 Methodology 265 12.4.1 Use of Human Stem Cell-Derived Cardiomyocytes 266 12.5 Translation of Effects on INaF: Relation to Conduction Velocity and Proarrhythmia 268 12.6 Conclusions 269 References 270 13 Circulating Biomarkers for Drug-Induced Cardiotoxicity: Reverse Translation from Patients to Nonclinical Species 279 Gül Erdemli, Haisong Ju, and Sarita Pereira 13.1 Introduction 279 13.2 Cardiac Troponins 280 13.3 Natriuretic Peptides 282 13.4 Novel/Exploratory Biomarkers: H-FABP, miRNA, and Genomic Biomarkers 285 13.5 Regulatory Perspective 286 13.6 Conclusions and Future Perspectives 288 References 289 14 The Mechanistic Basis of hERG Blockade and the Proarrhythmic Effects Thereof 295 Robert A. Pearlstein, K. Andrew MacCannell, Qi-Ying Hu, Ramy Farid, and José S. Duca 14.1 Introduction 295 14.1.1 The Role of hERG Dysfunction/Blockade in Promoting Early After Depolarizations 296 14.1.2 The Dynamics of hERG Blockade 301 14.1.3 Simulations of the Human Cardiac AP in the Presence of hERG Blockade 303 14.1.4 Estimation of Proarrhythmic hERG Occupancy Levels Based on AP Simulations 304 14.1.5 Novel Insights about the Causes of Inadvertent hERG Binding Function 305 14.1.6 Implications of Our Findings for hERG Safety Assessment 313 14.1.7 Conclusion and Future Directions 324 References 324 Section 4 Kinase Antitargets 329 15 Introduction to Kinase Antitargets 331 Mark C. Munson References 360 16 Clinical and Nonclinical Adverse Effects of Kinase Inhibitors 365 Douglas A. Keller, Richard J. Brennan, and Karen L. Leach 16.1 Introduction 365 16.2 Perspectives on the Clinical Safety of Kinase Inhibitor Therapy 371 16.3 Adverse Effects of Kinase Inhibitor Drugs 372 16.3.1 Hepatic Toxicity 372 16.3.2 Thyroid Toxicity 377 16.3.3 Bone and Tooth Toxicity 379 16.3.4 Cardiovascular Toxicity 380 16.3.5 Cutaneous Toxicity 380 16.3.6 Developmental and Reproductive Toxicity 383 16.3.7 Gastrointestinal Toxicity 385 16.3.8 Hematopoietic Toxicity 385 16.3.9 Ocular Toxicity 387 16.3.10 Pulmonary Toxicity 388 16.3.11 Renal Toxicity 389 16.4 Derisking Strategies for Kinase Inhibitor Toxicity 389 16.5 Concluding Remarks 391 References 391 17 Cardiac Side Effects Associated with Kinase Proteins and Their Signaling Pathways 401 Roy J. Vaz and Vinod F. Patel 17.1 A Case Study 401 17.2 Introduction 402 17.3 Cardiac-Specific Kinase Antitargets 404 17.3.1 Preclinical Findings in Genetically Modified or KI-Treated Mice 404 17.3.2 Clinical Findings of Kinase Inhibitors on the Heart and Their Mechanistic Understandings 404 17.4 Current and Future Directions 409 17.4.1 Preclinical Safety and Clinical Outcome Predictions 409 17.5 Conclusions 410 References 411 18 Case Studies: Selective Inhibitors of Protein Kinases – Exploiting Demure Features 413 Ellen R. Laird 18.1 Introduction 413 18.2 Case I: Indane Oximes as Selective B-Raf Inhibitors 414 18.3 Case II: ARRY-380 (ONT-380) – an ErbB2 Agent that Spares EGFR 420 18.4 Case III: Discovery of GDC-0068 (Ipatasertib), a Potent and Selective ATP-Competitive Inhibitor of AKT 424 18.5 Concluding Remarks 428 References 429 Section 5 Examples of Clinical Translation 435 19 Torcetrapib and Dalcetrapib Safety: Relevance of Preclinical In Vitro and In Vivo Models 437 Eric J. Niesor, Andrea Greiter-Wilke, and Lutz Müller 19.1 Introduction 437 19.2 Effect of Torcetrapib on Blood Pressure 437 19.3 In Vitro Studies 438 19.3.1 Direct Effect of Torcetrapib on Aldosterone Production In Vitro in Cultured H295R Adrenal Corticocarcinoma Cells 439 19.3.2 Molecular Mechanism of Torcetrapib Induction of Aldosterone Secretion 439 19.3.3 Development of Reproducible In Vitro Screening Models for Increase in Aldosterone and Cyp11B2 mRNA in a Human Adrenal Corticocarcinoma Cell Line 440 19.3.4 Application of In Vitro Models for the Successful Derisking of Dalcetrapib, Anacetrapib, and Evacetrapib 440 19.4 In Vivo Studies 441 19.4.1 Effect of Torcetrapib on Aldosterone and BP 441 19.4.2 Molecular Mechanisms of Torcetrapib-Induced BP Increase 444 19.5 General Safety Risk with Increased Aldosterone and BP 447 19.5.1 Inappropriate Increase in Aldosterone Secretion May Increase CV Risks 447 19.6 Relevance of BP and Aldosterone Preclinical Models to Clinical Observation with Dalcetrapib and Anacetrapib 448 19.7 Similarities between Potent CETPi and Halogenated Hydrocarbons 449 19.7.1 The Macrophage Scavenger Receptor MARCO, a Possible Antitarget for Dalcetrapib, and Its Relevance to Humans 450 19.8 Conclusions 451 References 451 20 Targets Associated with Drug-Related Suicidal Ideation and Behavior 457 Andreas Hartmann, Steven Whitebread, Jacques Hamon, Alexander Fekete, Christian Trendelenburg, Patrick Y. Müller, and László Urbán 20.1 Introduction 457 20.2 Targets Associated with Increased Suicidal Intent and Behavior 458 20.2.1 G-Protein-Coupled Receptors 458 20.2.2 Transporters 466 20.2.3 Ion Channels 469 20.3 Conclusions 472 References 473 Index 479

Rezension

“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.” (ChemMedChem, 1 October 2015)

Autorenportrait

Laszlo Urban received his MD and PhD in neurophysiology/neuropharmacology in Hungary, and was visiting professor at Duke University between 1987 and 1989. He is currently global head of Preclinical Safety Profiling at the Novartis Institutes for Biomedical Research, Cambridge, USA, and was previously the Deputy Head of the Novartis Institute for Medical Sciences in London, UK. Dr. Urban has over 130 scientific articles, book chapters and patents to his name. Roy J. Vaz received his PhD in organic chemistry from the University of Florida, Gainesville, an MBA from the University of Illinois, and most recently an MS in molecular biology from Lehigh University, USA. He is currently a senior distinguished scientist at Sanofi Pharmaceuticals in Waltham, MA, and was previously Director of the Investigative Product Optimization department under Aventis. He has worked at Bristol-Myers Squibb as Principal Scientist as well as at Tripos, Inc, as a research scientist. Dr. Vaz has authored or co-authored around 45 publications in peer-reviewed journals, eight book chapters and several patents. Vinod Patel gained his BSc in applied chemistry from Leicester Polytechnic, and a PhD in synthetic organic chemistry from Nottingham University, UK. He took up a post-doctoral fellowship at the University of Rochester, NY, USA, before joining Eli Lilly & Company, where he spent the next nine years as a medicinal chemist in the oncology division. He then joined Kinetix Pharmaceuticals, which was acquired by Amgen and Dr. Patel joined their new Cambridge facility as head of medicinal chemistry. In 2011, he joined Sanofi oncology research as head of medicinal chemistry where he is currently head of chemical research in lead generation candidate realization. Dr. Patel has over 50 publications and some 50 patents to his name.

Back cover copy

With 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. 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 ion-channel & transporters 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. 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.