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Preface XVII
Introduction XIX
List of Contributors XXV
Abbreviations XXIX
Part I General Aspects of Analogue-Based Drug Discovery 1
1 Analogues as a Means of Discovering New Drugs
Camille G. Wermuth 		3
1.1 Designing of Analogues 3
1.1.1 Analogues Produced by Homologous Variations 3
1.1.1.1 Homology Through Monoalkylation 3
1.1.1.2 Polymethylenic Bis-Ammonium Compounds: Hexa- and Decamethonium 3
1.1.1.3 Homology in Cyclic Compounds 4
1.1.2 Analogues Produced by Vinylogy 4
1.1.2.1 Zaprinast Benzologues 5
1.1.3 Analogues Produced by Isosteric Variations 5
1.1.3.1 The Dominant Parameter is Structural 5
1.1.3.2 The Dominant Parameter is Electronic 6
1.1.3.3 The Dominant Parameter is Lipophilicity 7
1.1.4 Positional Isomers Produced as Analogues 7
1.1.5 Optical Isomers Produced as Analogues 8
1.1.5.1 Racemic Switches 8
1.1.5.2 Specific Profile for Each Enantiomer 8
1.1.6 Analogues Produced by Ring Transformations 9
1.1.7 Twin Drugs 9
1.2 The Pros and Cons of Analogue Design 10
1.2.1 The Success is Almost Warranted 10
1.2.2 The Information is Available 11
1.2.3 Financial Considerations 11
1.2.4 Emergence of New Properties 12
1.3 Analogue Design as a Means of Discovering New Drugs 12
1.3.1 New Uses for Old Drugs 12
1.3.2 The PASS Program 14
1.3.3 New Leads from Old Drugs: The SOSA Approach 14
1.3.3.1 Definition 14
1.3.3.2 Rationale 15
1.3.3.3 Availability 15
1.3.3.4 Examples 15
1.3.3.4 Discussion 18
1.4 Conclusion 20
2 Drug Likeness and Analogue-Based Drug Discovery
John R. Proudfoot 		25
3 Privileged Structures and Analogue-Based Drug Discovery
Hugo Kubinyi 		53
3.1 Introduction 53
3.2 Drugs from Side Effects 54
3.3 Agonists and Antagonists 55
3.4 Privileged Structures 57
3.5 Drug Action on Target Classes 58
3.5.1 GPCR Ligands 59
3.5.2 Nuclear Receptor Ligands 61
3.5.3 Integrin Ligands 61
3.5.4 Kinase Inhibitors 63
3.5.5 Phosphodiesterase Inhibitors 64
3.5.6 Neurotransmitter Uptake Inhibitors 65
3.6 Summary and Conclusions 65
Part II Selected Examples of Analogue-Based Drug Discoveries 69
1 Development of Anti-Ulcer H2-Receptor Histamine Antagonists
C. Robin Ganellin 		71
1.1 Introduction 71
1.2 The Prototype Drug, Burimamide, Defined Histamine H2-Receptors 71
1.3 The Pioneer Drug, Cimetidine: A Breakthrough for Treating Peptic Ulcer Disease 72
1.4 Ranitidine: The First Successful Analogue of H2 Antagonists 73
1.5 The Discovery of Tiotidine and Famotidine 76
1.6 Other Compounds 77
1.7 The Use of H2-Receptor Histamine Antagonists as Medicines 78
2 Esomeprazole in the Framework of Proton-Pump Inhibitor Development
Per Lindberg and Enar Carlsson 		81
2.1 Towards Omeprazole: The First Proton-Pump Inhibitor 81
2.2 The Treatment of Acid-Related Disorders Before Losec® 81
2.3 Pioneer Research at Hässle during the 1960s and 1970s 83
2.3.1 Toxicological Challenges 86
2.3.2 Discovery of H+, K+-ATPase: The Gastric Proton Pump 87
2.3.3 Analogue Optimization 87
2.4 The Development of Omeprazole 89
2.4.1 Further Toxicological Challenges and the Halt of the Clinical Program 89
2.4.2 Resumption of Clinical Studies 90
2.4.3 Omeprazole Reaches the Market and Supersedes H2-Receptor Antagonists 90
2.5 The Unique Action of Omeprazole 91
2.5.1 Inhibition of the Final Step 91
2.5.2 Omeprazole Binds Strongly to the H+, K+-ATPase 91
2.5.3 Inhibition of Acid Secretion and H+, K+-ATPase Activity 92
2.5.4 Omeprazole Concentrates and Transforms in Acid 93
2.5.5 Disulfide Enzyme–Inhibitor Complex on the Luminal Side 93
2.5.6 Short Half-Life in Plasma and Long Half-Life for Enzyme–Inhibitor Complex 93
2.5.7 Mechanism at the Molecular Level 94
2.5.8 The "Targeted Prodrug" Omeprazole means a Highly Specific Action 96
2.6 pH-Stability Profile 97
2.7 Omeprazole Analogues Synthesized by Other Companies 98
2.8 Omeprazole: A Need for Improvement? 103
2.8.1 The Omeprazole Follow-Up Program 103
2.8.2 No Good Alternative to the Omeprazole Structural Template 103
2.8.3 Chemical Approach 104
2.8.4 Synthesis and Screening 105
2.8.5 Isomers Seemed Unattractive 106
2.8.6 Isomer Pharmacokinetics and Pharmacodynamics in Animals 106
2.8.7 The Key Experiment in Man 107
2.8.8 Production of Esomeprazole (Mg Salt) 109
2.8.9 Omeprazole Isomers: Differences in Clearance and Metabolic Pattern 109
2.9 Summary 111
3 The Development of a New Proton-Pump Inhibitor: The Case History of Pantoprazole
Jörg Senn-Bilfinger and Ernst Sturm 		115
3.1 Introduction 115
3.2 History of Gastrointestinal Research at Byk Gulden 117
3.2.1 The Antacids and Cytoprotectives Projects and the Set-Up of In-Vivo Ulcer Models 117
3.2.2 Decision to Concentrate on Anti-Secretory Treatments and the Study of Compounds with an Unknown Mechanism of Action 118
3.3 Identification of the First PPI Project Candidates 121
3.3.1 Optimizing the Benzimidazole Moiety 121
3.3.2 Impact of the First PPI Project Compounds 123
3.4 Elucidation of the Mechanism of Action of PPIs 125
3.4.1 A Surprising Interrelationship Between Stability and Activity 125
3.4.2 Isolation and Identification of the Active Principle of the PPIs 125
3.5 Identification of Pantoprazole as a Candidate for Development 128
3.5.1 Optimizing the Pyridine Moiety and the First Synthesis of Pantoprazole 128
3.5.2 Selection Criteria 129
3.5.3 The Selection of Pantoprazole and Internal Competition with SK&F95601 130
3.5.4 Toxicological Problems: Project Development at Risk 131
3.5.5 Benefits of Pantoprazole for the Patient 132
3.5.6 Summary 132
3.6 Outlook on Further Developments 133
4 Optimizing the Clinical Pharmacologic Properties of the HMG-CoA Reductase Inhibitors
Sándor Kerpel-Fronius and János Fischer 		137
4.1 Introduction 137
4.2 Medicinal chemistry of the Statins 138
4.3 Clinical and Pharmacologic Properties of the Statin Analogues 142
4.3.1 Fibrate Coadministration 148
4.4 Clinical Efficacy of the Statins 149
5 Optimizing Antihypertensive Therapy by Angiotensin Receptor Blockers
Csaba Farsang and János Fischer 		157
5.1 Medicinal Chemistry 157
5.2 Clinical Results with Angiotensin II Antagonists 160
5.2.1 Mechanisms of Action 160
5.2.1.1 Other Effects of ARBs 161
5.2.2 Target Organ Protection 162
5.2.2.1 Left Ventricular Hypertrophy 162
5.2.2.2 Diabetic and Nondiabetic Nephropathy 162
5.2.2.3 Diabetes Prevention 162
5.2.2.4 Coronary Heart Disease (CHD) 162
5.2.2.5 Congestive Heart Failure 162
5.2.2.6 Stroke Prevention and Other CNS Effects 163
5.3 Differences Among Angiotensin AT1 Receptor Blockers 163
5.3.1 Structural Differences 163
5.3.2 AT1 Receptor Antagonism 164
5.3.3 Pharmacokinetics/Dosing Considerations 164
5.3.4 Drug Interactions/Adverse Effects 165
5.3.5 Efficacy in Hypertension 165
5.4 Summary 166
6 Optimizing Antihypertensive Therapy by Angiotensin-Converting Enzyme Inhibitors
Sándor Alföldi and János Fischer 		169
6.1 Medicinal Chemistry of ACE-inhibitors 169
6.2 Clinical Results with ACE-Inhibitors 173
6.2.1 Hemodynamic Effects 173
6.2.2 Effects of ACE-Inhibitors 174
6.2.2.1 Hypotension 174
6.2.2.2 Dry Cough 174
6.2.2.3 Hyperkalemia 174
6.2.2.4 Acute Renal Failure 175
6.2.2.5 Proteinuria 175
6.2.2.6 Angioedema 175
6.2.2.7 Teratogenic Effects 175
6.2.2.8 Other Side Effects 175
6.2.3 Contraindications 176
6.2.4 Drug Interactions 176
6.3 Differences Among ACE-Inhibitors 177
6.4 Summary and Outlook 179
7 Case Study of Lacidipine in the Research of New Calcium Antagonists
Giovanni Gaviraghi 		181
7.1 Introduction 181
7.2 Dihydropyridine Calcium Channel-Blocking Agents 182
7.2.1 Nifedipine 182
7.2.2 Felodipine 183
7.2.3 Isradipine 183
7.2.4 Nimodipine 184
7.2.5 Nisoldipine 184
7.2.6 Amlodipine 185
7.2.7 Lacidipine 185
7.2.8 Lercanidipine 185
7.2.9 Manidipine 186
7.3 Lacidipine: A Long-Lasting Calcium Channel-Blocking Drug: Case Study 187
7.3.1 The Lacidipine Project 188
7.3.2 Synthesis 190
7.3.3 The Pharmacological Profile of Lacidipine 190
7.4 Conclusion 191
8 Selective Beta-Adrenergic Receptor-Blocking Agents
Paul W. Erhardt and Lajos Matos 		193
8.1 Introduction 193
8.2 Beta-1 Selective Blockers 201
8.2.1 Atenolol 201
8.2.1.1 Discovery 201
8.2.1.2 Synthesis 203
8.2.1.3 Clinical Pharmacology 203
8.2.2 Betaxolol 206
8.2.2.1 Discovery 206
8.2.2.2 Synthesis 209
8.2.2.3 Clinical Pharmacology 210
8.2.3 Celiprolol 211
8.2.3.1 Discovery 211
8.2.3.2 Synthesis 214
8.2.3.3 Clinical Pharmacology 215
8.2.4 Nebivolol 217
8.2.4.1 Discovery 217
8.2.4.2 Synthesis 218
8.2.4.3 Clinical Pharmacology 220
8.3 Accumulated Structure–Activity Relationships 222
8.4 Summary 226
9 Case Study: "Esmolol Stat"
Paul W. Erhardt 		233
9.1 Introduction 233
9.2 Pharmacological Target 234
9.3 Chemical Target 234
9.3.1 Internal Esters 234
9.3.2 External Esters 236
9.3.3 Structure–Activity Relationships 237
9.4 Chemical Synthesis 240
9.5 Pharmacology and Clinical Profile 241
9.6 Summary and Some Lessons for Today 243
9.6.1 Compound Libraries 243
9.6.2 Biological Testing 244
9.6.3 SAR 244
10 Development of Organic Nitrates for Coronary Heart Disease
László Dézsi 		247
10.1 Introduction 247
10.2 Empirical Observations Leading to the Therapeutic Use of Classic Nitrovasodilators 247
10.3 Isoamyl Nitrite: The Pioneer Drug 248
10.4 Nitroglycerin (Glyceryl Trinitrate): The Most Successful Analogue 248
10.5 Isosorbide Dinitrate: A Viable Analogue with Prolonged Action 249
10.6 Isosorbide Mononitrate: The Metabolite of Isosorbide Dinitrate 250
10.7 Nicorandil: The Potassium Channel Opener Analogue with a Broad Cardiovascular Spectrum 251
10.8 Cardiovascular Efficacy of Organic Nitrates 252
10.9 Mechanism of Action of Organic Nitrates 253
10.10 Tolerance to Organic Nitrates 255
10.11 Concluding Remarks 256
11 Development of Opioid Receptor Ligands
Christopher R. McCurdy 		259
11.1 Introduction 259
11.2 Pharmacology Related to the Classic Opioid Receptors. 261
11.3 Alkaloids from the Latex of Papaver somniferum Initiate Research 261
11.4 Morphine: The Prototype Opioid Ligand 262
11.4.1 Initial Studies of Morphine Analogues 263
11.5 Structure–Activity Relationships of Morphine Derivatives 265
11.6 Synthetic Analogues of Thebaine Further Define Morphinan SAR 266
11.7 Compounds of the Morphinan Skeleton Produce New Agents 269
11.8 Further Reduction of the Morphinan Skeleton Produced the Benzomorphans 270
11.9 Another Simplified Version of Morphine Creates a New Class of Opioid Ligand 271
11.10 A Breakthrough in the Structural Design of Opioid Ligands 271
11.11 Discovery of the 4-Anilidopiperidines 273
11.12 Phenylpropylamines: The Most Stripped-Down Opioids Still Related to Morphine 273
11.13 The Use of Opioid Analgesics in Clinical Practice: Hope of the Future 274
12 Stigmines
Zeev Tashma 		277
12.1 Historical Background 277
12.2 Pharmacological Activities of Physostigmine 278
12.3 Chemistry and Biochemistry of Physostigmine 279
12.4 Interaction of Acetylcholinesterase with Carbamates 280
12.5 SAR of the Eseroline Moiety, and the Development of Miotine 282
12.6 The Development of Quaternary Carbamates for Myasthenia Gravis 283
12.7 Carbamates as Pre-Exposure Treatment against Organophosphate Intoxication 284
12.8 Carbamates as Insecticides 286
12.8.1 Structural Features 287
12.9 Carbamates in the Treatment of Alzheimer's Disease 287
12.9.2 Close Derivatives of Physostigmine 288
12.9.3 Rivastigmine 289
13 Structural Analogues of Clozapine
Béla Kiss and István Bitter 		297
13.1 Introduction 297
13.2 Clozapine: The Prototype "Atypical" Antipsychotic; Some Chemical Aspects 299
13.3 Preclinical Aspects 300
13.3.1 Multireceptor Profile: In-Vitro, In-Vivo Similarities and Differences 300
13.3.2 The Availability of Data 304
13.3.3 Dopamine D2 versus Serotonin 5-HT2A Affinity 304
13.3.4 Affinity to other Receptors 306
13.3.5 Inverse Agonism 306
13.3.6 Receptor Affinity of Metabolites and Clinical Action 307
13.4 Clinical Aspects 307
13.4.1 Terminology 307
13.4.2 Indications 308
13.4.3 Dosage 308
13.4.4 Clinical Efficacy in Schizophrenia 308
13.4.5 Clinical Efficacy in Bipolar Disorder (Especially in Mania) 309
13.4.6 Adverse Events 310
13.5 Summary and Conclusions 310
14 Quinolone Antibiotics: The Development of Moxifloxacin
Uwe Petersen 		315
14.1 Introduction 315
14.2 Aims 320
14.3 The Chemical Evolution of Moxifloxacin 321
14.4 Synthetic Routes 338
14.4.1 S,S–2,8-Diazabicyclo[4.3.0]nonane 338
14.4.2 Preparation of BAY X 8843 36 and its Analogues 339
14.4.3 Preparation of Moxifloxacin Hydrochloride 47 339
14.5 The Physicochemical Properties of Moxifloxacin 342
14.6 The Microbiological and Clinical Properties of Moxifloxacin 344
14.6.1 Mycobacterium tuberculosis 347
14.6.2 Skin Infections 347
14.6.3 Ophthalmology 348
14.6.4 Dental Medicine 348
14.7 Pharmacokinetics/Pharmacodynamics of Moxifloxacin 348
14.8 Development of Resistance to Moxifloxacin 350
14.9 Safety and Tolerability of Moxifloxacin 352
14.10 Metabolism, Excretion and Biodegradability of Moxifloxacin 353
14.11 Future Prospects for Quinolones 355
14.12 Summary and Conclusions 356
15 The Development of Bisphosphonates as Drugs
Eli Breuer 		371
15.1 Historical Background 371
15.2 Discovery of the Biological Activity of Pyrophosphate and of Bisphosphonates 372
15.3 Bone-Related Activity of Bisphosphonates 372
15.3.1 Overview 372
15.3.2 Osteolytic Bone Diseases 373
15.3.2.1 Osteoporosis 373
15.3.2.2 Osteolytic Tumors 373
15.3.2.3 Paget's Disease 375
15.3.3 Structure–Activity Relationships 375
15.3.3.1 The Molecular Skeletons of Bisphosphonates 375
15.3.3.2 Phosphonic Acid Groups 375
15.3.3.3 The Geminal Hydroxy Group 375
15.3.3.4 Nitrogen-Containing Side Chain 375
15.3.3.5 Structure–Activity Relationships of BPs: A Summary 376
15.3.4 Inhibition of Bone Resorption: The Mechanisms of Action 377
15.3.5 Clinical Pharmacology of Bisphosphonates 378
15.3.6 Bisphosphonates in Clinical Use 379
15.4 Miscellaneous Biological Aspects of Bisphosphonates 379
15.4.1 Bisphosphonates as Vehicles for Delivering Drugs to Bone 379
15.4.2 Bisphosphonates as Potential Drugs for other Indications 379
15.4.2.1 Antiviral Drugs 381
15.4.2.2 Bisphosphonate Inositol-Monophosphatase Inhibitor: A Potential Drug for Bipolar Disorders 381
15.4.2.3 Hypocholesterolemic Bisphosphonates (Squalene Synthase Inhibitors) 381
15.4.2.4 Antiparasitic Drugs 381
15.4.2.5 Anti-Inflammatory and Anti-Arthritic Bisphosphonates 382
15.4.2.6 Cardiovascular Applications of Bisphosphonates 382
15.5 Conclusions 382
16 Cisplatin and its Analogues for Cancer Chemotherapy
Sándor Kerpel-Fronius 		385
16.1 Introduction 385
16.2 Cisplatin 385
16.2.1 Discovery 385
16.2.2 Structure 386
16.2.3 Mechanism of Action 386
16.2.4 Pharmacokinetics 387
16.2.5 Clinical Efficacy 387
16.2.6 Adverse Effects 388
16.3 Carboplatin 389
16.3.1 Development 389
16.3.2 Administration and Pharmacokinetics 389
16.3.4 Adverse Effects 390
16.3.5 Clinical Efficacy 390
16.4 Oxaliplatin 390
16.4.1 Development 390
16.4.2 Cellular Resistance to Various Pt Analogues 391
16.4.3 Metabolism and Pharmacokinetics 392
16.4.4 Adverse Effects 392
16.4.5 Clinical Efficacy 392
16.5 Summary 393
17 The History of Drospirenone
Rudolf Wiechert 		395
17.1 General Development 395
17.2 Syntheses 397
18 Histamine H1 Blockers: From Relative Failures to Blockbusters Within Series of Analogues
Henk Timmerman 		401
18.1 Introduction 401
18.2 The First Antihistamines 402
18.3 Diphenhydramine as a Skeleton for Antihistamines 403
18.3.1 The Diaryl Group 404
18.3.2 The Linker 406
18.3.3 The Basic Group 406
18.3.4 The Analogue Principle 407
18.3.5 The Analogue Principle in Perspective 409
18.4 The New Antihistamines 411
18.5 Antihistamines for Which the Analogue Principle Does not Seem to Work 415
18.6 Inverse Agonism 415
18.7 A Further Generation of Antihistamines? 416
18.8 Conclusions 417
19 Corticosteroids: From Natural Products to Useful Analogues
Zoltán Tuba, Sándor Mahó, and Csaba Sánta 		419
19.1 Introduction 419
19.2 Corticosteroid Analogues 420
19.2.1 Cortisone 422
19.2.2 Hydrocortisone 423
19.2.3 Prednisone and Prednisolone 424
19.2.4 Fludrocortisone 424
19.2.5 Triamcinolone and Triamcinolone Acetonide 425
19.2.6 Dexamethasone 426
19.2.7 Betamethasone 427
19.2.8 Beclomethasone Dipropionate 428
19.2.9 Methylprednisolone 429
19.2.10 Fluocinolone Acetonide, Flunisolide, Fluocortin-21-Butylate and Flumetasone 429
19.2.11 Budesonide 431
19.2.12 Halobetasol Propionate 432
19.2.13 Mometasone Furoate 433
19.2.14 Fluticasone Propionate 434
19.2.15 Loteprednol Etabonate 435
19.2.16 Ciclesonide 436
19.3 Summary 437
Part III Table of Selected Analogue Classes
Erika M. Alapi and János Fischer 		441
Index 553

 
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