Reactive Drug Metabolites

Preface XIII

A Personal Foreword XV

1 Origin and Historical Perspective on Reactive Metabolites 1

Abbreviations 1

1.1 Mutagenesis and Carcinogenesis 1

1.2 Detection of Reactive Metabolites 3

1.3 Induction and Inhibition: Early Probes for Reactive Metabolites and Hepatotoxicants 4

1.4 Covalent Binding and Oxidative Stress: Possible Mechanisms of Reactive Metabolite Cytotoxicity 5

1.5 Activation and Deactivation: Intoxication and Detoxification 6

1.6 Genetic Influences on Reactive Metabolite Formation 6

1.7 Halothane: the Role of Reactive Metabolites in Immune-Mediated Toxicity 7

1.8 Formation of Reactive Metabolites, Amount Formed, and Removal of Liability 8

1.9 Antibodies: Possible Clues but Inconclusive 8

1.10 Parent Drug and Not Reactive Metabolites, Complications in Immune-Mediated Toxicity 9

1.11 Reversible Pharmacology Should not be Ignored as a Primary Cause of Side Effects 10

1.12 Conclusions: Key Points in the Introduction 10

References 11

2 Role of Reactive Metabolites in Genotoxicity 13

Abbreviations 13

2.1 Introduction 13

2.2 Carcinogenicity of Aromatic and Heteroaromatic Amines 13

2.3 Carcinogenicity of Nitrosamines 17

2.4 Carcinogenicity of Quinones and Related Compounds 19

2.5 Carcinogenicity of Furan 23

2.6 Carcinogenicity of Vinyl Halides 26

2.7 Carcinogenicity of Ethyl Carbamate 26

2.8 Carcinogenicity of Dihaloalkanes 28

2.9 Assays to Detect Metabolism-Dependent Genotoxicity in Drug Discovery 28

2.10 Case Studies in Eliminating Metabolism-Based Mutagenicity in Drug Discovery Programs 29

References 36

3 Bioactivation and Inactivation of Cytochrome P450 and Other Drug-Metabolizing Enzymes 43

Abbreviations 43

3.1 Introduction 43

3.2 Pharmacokinetic and Enzyme Kinetic Principles Underlying Mechanism-Based Inactivation and Drug–Drug Interactions 44

3.2.1 Enzyme Kinetic Principles of Mechanism-Based Inactivation 44

3.2.2 Pharmacokinetic Principles Underlying DDIs Caused by Mechanism-Based Inactivation 46

3.3 Mechanisms of Inactivation of Cytochrome P450 Enzymes 47

3.3.1 Quasi-Irreversible Inactivation 47

3.3.2 Heme Adducts 48

3.3.3 Protein Adducts 49

3.4 Examples of Drugs and Other Compounds that are Mechanism-Based Inactivators of Cytochrome P450 Enzymes 49

3.4.1 Amines 49

3.4.2 Methylenedioxyphenyl Compounds 51

3.4.3 Quinones, Quinone Imines, and Quinone Methides 52

3.4.4 Thiophenes 53

3.4.5 Furans 55

3.4.6 Alkynes 56

3.4.7 2-Alkylimidazoles 57

3.4.8 Other Noteworthy Cytochrome P450 Inactivators 58

3.5 Mechanism-Based Inactivation of Other Drug-Metabolizing Enzymes 60

3.5.1 Aldehyde Oxidase 60

3.5.2 Monoamine Oxidases 61

3.6 Concluding Remarks 64

References 65

4 Role of Reactive Metabolites in Drug-Induced Toxicity – The Tale of Acetaminophen, Halothane, Hydralazine, and Tienilic Acid 71

Abbreviations 71

4.1 Introduction 71

4.2 Acetaminophen 71

4.2.1 Metabolism of Acetaminophen 72

4.2.2 Metabolic Activation of Acetaminophen 73

4.3 Halothane 75

4.3.1 Metabolism of Halothane 76

4.3.2 Hepatotoxicity following Halothane Administration 78

4.4 Hydralazine 79

4.5 Tienilic Acid 82

References 84

5 Pathways of Reactive Metabolite Formation with Toxicophores/-Structural Alerts 93

Abbreviations 93

5.1 Introduction 93

5.2 Intrinsically Reactive Toxicophores 93

5.2.1 Electrophilic Functional Groups 94

5.2.2 Metal Complexing Functional Groups 96

5.3 Toxicophores that Require Bioactivation to Reactive Metabolites 98

5.3.1 Aromatic Amines (Anilines) 98

5.3.2 ortho- and para-Aminophenols 101

5.3.3 Nitroarenes 103

5.3.4 Hydrazines 105

5.3.5 Five-Membered Heteroaromatic Rings 107

5.3.5.1 Furans 107

5.3.5.2 Thiophenes 109

5.3.5.3 Thiazoles and 2-Aminothiazoles 109

5.3.5.4 3-Alkyl Pyrrole and 3-Alkylindole Derivatives 112

5.3.5.5 1,3-Benzdioxole (Methylenedioxyphenyl) Motif 115

5.3.6 Terminal Alkenes and Alkynes 117

5.4 Concluding Remarks 121

References 121

6 Intrinsically Electrophilic Compounds as a Liability in Drug Discovery 131

Abbreviations 131

6.1 Introduction 131

6.2 Intrinsic Electrophilicity of b-Lactam Antibiotics as a Causative Factor in Toxicity 131

6.3 Intrinsically Electrophilic Compounds in Drug Discovery 133

6.3.1 Linking Innate Electrophilicity with Drug Toxicity 135

6.4 Serendipitous Identification of Intrinsically Electrophilic Compounds in Drug Discovery 136

References 141

7 Role of Reactive Metabolites in Pharmacological Action 145

Abbreviations 145

7.1 Introduction 145

7.2 Drugs Activated Nonenzymatically and by Oxidative Metabolism 145

7.2.1 Proton Pump Inhibitors 145

7.2.2 Nitrosoureas 147

7.2.3 Imidazotriazenes 148

7.2.4 Thienotetrahydropyridines 150

7.2.5 Oxazaphosphorines 152

7.2.6 N,N,N0,N0,N0,N0-Hexamethylmelamine 153

7.3 Bioreductive Activation of Drugs 153

7.3.1 Bioreduction to Radical Intermediates 157

7.3.1.1 Tirapazamine 157

7.3.1.2 Anthracyclines 157

7.3.1.3 Enediynes 158

7.3.1.4 Artemisinin Derivatives 166

7.3.2 Bioreductive Activation to Electrophilic Intermediates 168

7.3.2.1 Mitomycins 168

7.3.2.2 Aziridinylbenzoquinones 170

7.3.2.3 Bioreductive Activation of Anthracyclines to Alkylating Species 173

7.3.2.4 Bioreductive Activation of Nitroaromatic Compounds 174

7.4 Concluding Remarks 175

References 176

8 Retrospective Analysis of Structure–Toxicity Relationships of Drugs 185

Abbreviations 185

8.1 Introduction 185

8.2 Irreversible Secondary Pharmacology 189

8.2.1 Common Structural Features: Carboxylic Acids 189

8.3 Primary Pharmacology and Irreversible Secondary Pharmacology 191

8.4 Primary or Secondary Pharmacology and Reactive Metabolites: the Possibility for False Structure–Toxicity Relationships 192

8.5 Multifactorial Mechanisms as Causes of Toxicity 196

8.6 Clear Correlation between Protein Target and Reactive Metabolites 197

8.7 Conclusion – Validation of Reactive Metabolites as Causes of Toxicity 198

References 200

9 Bioactivation and Natural Products 203

Abbreviations 203

9.1 Introduction 203

9.2 Well-Known Examples of Bioactivation of Compounds Present in Herbal Remedies 205

9.2.1 Germander and Teucrin A 205

9.2.2 Pennyroyal Oil and Menthofuran 207

9.2.3 Aristolochia and Aristolochic Acid 208

9.2.4 Comfrey, Coltsfoot, and Pyrrolizidine Alkaloids 210

9.3 Well-Known Examples of Bioactivation of Compounds Present in Foods 212

9.3.1 Cycasin 212

9.3.2 Aflatoxin 214

9.3.3 3-Methylindole 216

9.3.4 Polycyclic Azaheterocyclic Compounds in Cooked Meats 216

9.3.5 Nitrosamines 219

9.4 Summary 220

References 220

10 Experimental Approaches to Reactive Metabolite Detection 225

Abbreviations 225

10.1 Introduction 225

10.2 Identification of Structural Alerts and Avoiding them in Drug Design 225

10.3 Assays for the Detection of Reactive Metabolites 227

10.3.1 Qualitative Electrophile Trapping Assays 227

10.3.2 Quantitative Electrophile Trapping Assays 230

10.3.3 Covalent Binding Assays 231

10.3.4 Detecting and Characterizing Bioactivation by Enzymes Other than Cytochrome P450 233

10.4 Other Studies that can Show the Existence of Reactive Metabolites 234

10.4.1 Metabolite Identification Studies 234

10.4.2 Radiolabeled Metabolism and Excretion In Vivo 235

10.4.3 Whole-Body Autoradiography and Tissue Binding 236

10.4.4 Inactivation of Cytochrome P450 Enzymes 237

10.5 Conclusion 237

References 238

11 Case Studies on Eliminating/Reducing Reactive Metabolite Formation in Drug Discovery 241

Abbreviations 241

11.1 Medicinal Chemistry Tactics to Eliminate Reactive Metabolite Formation 241

11.2 Eliminating Reactive Metabolite Formation on Heterocyclic Ring Systems 242

11.2.1 Mechanism(s) of Thiazole Ring Bioactivation and Rational Chemistry Approaches to Abolish Reactive Metabolite Formation 242

11.2.2 Mechanism(s) of Isothiazole Ring Bioactivation and Rational Chemistry Approaches to Abolish Reactive Metabolite Formation 249

11.3 Medicinal Chemistry Strategies to Mitigate Bioactivation of Electron-Rich Aromatic Rings 251

11.4 Medicinal Chemistry Strategies to Mitigate Bioactivation on a Piperazine Ring System 256

11.5 4-Fluorofelbamate as a Potentially Safer Alternative to Felbamate 258

11.6 Concluding Remarks 263

References 263

12 Structural Alert and Reactive Metabolite Analysis for the Top 200 Drugs in the US Market by Prescription 269

Abbreviations 269

12.1 Introduction 269

12.2 Structural Alert and Reactive Metabolite Analyses for the Top 20 Most Prescribed Drugs in the United States for the Year 2009 270

12.2.1 Daily Dose Trends 270

12.2.2 Presence of Structural Alerts 270

12.2.3 Evidence for Metabolic Activation to Reactive Metabolites 275

12.3 Insights Into the Excellent Safety Records for Reactive Metabolite–Positive Blockbuster Drugs 280

12.4 Structural Alert and Reactive Metabolite Analyses for the Remaining 180 Most Prescribed Drugs 282

12.4.1 Structural Alert and/or Reactive Metabolite “False Positives” 289

12.5 Structure Toxicity Trends 302

12.5.1 Meloxicam versus Sudoxicam 304

12.5.2 Zolpidem versus Alpidem 304

12.5.3 Quetiapine versus Olanzapine versus Clozapine 304

References 306

13 Mitigating Toxicity Risks with Affinity Labeling Drug Candidates 313

Abbreviations 313

13.1 Introduction 313

13.2 Designing Covalent Inhibitors 313

13.2.1 Selection of Warheads 316

13.2.2 Reversible Covalent Modification 322

13.3 Optimization of Chemical Reactivity of the Warhead Moiety 326

13.3.1 Experimental Approaches 326

13.3.2 In Silico Approaches 328

13.3.3 Additional Derisking Factors 329

13.4 Concluding Remarks 329

References 330

14 Dealing with Reactive Metabolite–Positive Compounds in Drug Discovery 335

Abbreviations 335

14.1 Introduction 335

14.2 Avoiding the Use of Structural Alerts in Drug Design 336

14.3 Structural Alert and Reactive Metabolite Formation 338

14.4 Should Reactive Metabolite–Positive Compounds be Nominated as Drug Candidates? 340

14.4.1 Impact of Competing, Detoxification Pathways 341

14.4.2 The Impact of Dose Size 342

14.4.3 Consideration of the Medical Need/Urgency 345

14.4.4 Consideration of the Duration of Treatment 345

14.4.5 Consideration of Novel Pharmacological Targets 346

14.5 The Multifactorial Nature of IADRs 348

14.6 Concluding Remarks 350

References 351

15 Managing IADRs – a Risk–Benefit Analysis 357

Abbreviations 357

15.1 Risk–Benefit Analysis 357

15.2 How Common is Clinical Drug Toxicity? 359

15.3 Rules and Laws of Drug Toxicity 363

15.4 Difficulties in Defining Cause and Black Box Warnings 365

15.5 Labeling Changes, Contraindications, and Warnings: the Effectiveness of Side Effect Monitoring 367

15.6 Allele Association with Hypersensitivity Induced by Abacavir: Toward a Biomarker for Toxicity 369

15.7 More Questions than Answers: Benefit Risk for ADRs 373

References 374

Index 377

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