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 ............... 3
Camille С Wermuth
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 ............ 25
John R. Proudfoot
3. Privileged Structures and Analogue-Based Drug Discovery .... 53
Hugo Kubinyi
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 ................................................ 71
C. Robin Canellin
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 ................................................ 81
Per Lindberg and Enar Carlsson
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 Hassle 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 ..................... 205
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 .......................... 115
Jörg Senn-Bilfmger and Ernst Sturm
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
HMC-CoA Reductase Inhibitors .............................. 137
Sándor Kerpel-Fronius and János Fischer
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 ......................................... 157
Csaba Farsang and János Fischer
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 .................... 365
5.4. Summary ............................................. 166
6. Optimizing Antihypertensive Therapy by Angiotensin-
Converting Enzyme Inhibitors .............................. 169
Sándor Alföldi and János Fischer
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 ............................................... 181
Giovanni Gaviraghi
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 ........ 193
Paul W. Erhardt and Lajos Matos
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" ................................ 233
Paul W. Erhardt
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 ................................................... 247
László Dézsi
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 .................... 259
Christopher R. McCurdy
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 ................................................. 277
Zeev Tashma
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 ......................... 297
Béla Kiss and István Bitter
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 .... 315
Uwe Petersen
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 ............... 371
Eli Breuer
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 ......................... 382
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 ....... 385
Sándor Kerpel-Fronius
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 ............................... 395
Rudolf Wiechert
17.1. General Development ................................. 395
17.2. Syntheses ........................................... 397
18. Histamine Hn Blockers: From Relative Failures to
Blockbusters Within Series of Analogues ................... 401
Henk Timmerman
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 .......................................... 419
Zoltán Tuba, Sándor Mahó, and Csaba Sánta
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 .................. 441
Erika M. Alapi and János Fischer
Index ......................................................... 553
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