Table of Contents
Foreword xi
Preface xiii
Contributors xv
1 THE ROLE OF MEDICINAL CHEMISTRY IN DRUG DISCOVERY 1John A. Lowe, III
1.1 Introduction 1
1.2 Hurdles in the Drug Discovery Process 2
1.3 The Tools of Medicinal Chemistry 3
1.4 The Role of Synthetic Chemistry in Drug Discovery 6
2 PROCESS RESEARCH: HOW MUCH? HOW SOON? 11Neal G. Anderson
2.1 Introduction 11
2.2 Considerations for Successful Scale-up to Tox Batches and Phase I Material 15
2.3 Considerations for Phase 2 Material and Beyond 16
2.4 Summary 26
I CANCER AND INFECTIOUS DISEASES
3 AROMATASE INHIBITORS FOR BREAST CANCER: EXEMESTANE (AROMASIN), ANASTROZOLE (ARIMIDEX), AND LETROZOLE (FEMARA) 31Jie Jack Li
3.1 Introduction 32
3.2 Synthesis of Exemestane 35
3.3 Synthesis of Anastrozole 36
3.4 Synthesis of Letrozole 37
4 QUINOLONE ANTIBIOTICS: LEVOFLOXACIN (LEVAQUIN), MOXIFLOXACIN (AVELOX), GEMIFLOXACIN (FACTIVE), AND GARENOXACIN (T-3811) 39Chris Limberakis
4.1 Introduction 40
4.2 Levofloxacin 47
4.3 Moxifloxacin 57
4.4 Gemifloxacin 60
4.5 Garenoxacin (T-3811): A Promising Clinical Candidate 64
5 TRIAZOLE ANTIFUNGALS: ITRACONAZOLE (SPORANOX), FLUCONAZOLE (DIFLUCAN), VORICONAZOLE (VFEND), AND FOSFLUCONAZOLE (PRODIF) 71Andrew S. Bell
5.1 Introduction 72
5.2 Synthesis of Itraconazole 74
5.3 Synthesis of Fluconazole 76
5.4 Synthesis of Voriconazole 77
5.5 Synthesis of Fosfluconazole 80
6 NON-NUCLEOSIDE HIV REVERSE TRANSCRIPTASE INHIBITORS 83Arthur Harms
6.1 Introduction 84
6.2 Synthesis of Nevirapine 85
6.3 Synthesis of Efavirenz 87
6.4 Synthesis of Delavirdine Mesylate 90
7 NEURAMINIDASE INHIBITORS FOR INFLUENZA: OSELTAMIVIR PHOSPHATE (TAMIFLU) AND ZANAMIVIR (RELENZA) 95Douglas S. Johnson and Jie Jack Li
7.1 Introduction 95
7.1.1 Relenza 97
7.1.2 Tamiflu 97
7.2 Synthesis of Oseltamivir Phosphate (Tamiflu) 99
7.3 Synthesis of Zanamivir (Relenza) 110
II CARDIOVASCULAR AND METABOLIC DISEASES
8 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS FOR TYPE 2 DIABETES 117Jin Li
8.1 Introduction 117
8.2 Synthesis of Rosiglitazone 121
8.3 Synthesis of Pioglitazone 122
8.4 Synthesis of Muraglitazar 124
9 ANGIOTENSIN AT1 ANTAGONISTS FOR HYPERTENSION 129Larry Yet
9.1 Introduction 130
9.2 Losartan Potassium 132
9.3 Valsartan 134
9.4 Irbesartan 135
9.5 Candesartan Cilexetil 136
9.6 Olmesartan Medoxomil 137
9.7 Eprosartan Mesylate 138
9.8 Telmisartan 139
10 LEADING ACE INHIBITORS FOR HYPERTENSION 143Victor J. Cee and Edward J. Olhava
10.1 Introduction 144
10.2 Synthesis of Enalapril Maleate 146
10.3 Synthesis of Lisinopril 147
10.4 Synthesis of Quinapril 148
10.5 Synthesis of Benazepril 150
10.6 Synthesis of Ramipril 151
10.7 Synthesis of Fosinopril Sodium 154
11 DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS FOR HYPERTENSION 159Daniel P. Christen
11.1 Introduction 160
11.2 Synthesis of Nifedipine (Adalat) 162
11.3 Synthesis of Felodepine (Plendil) 163
11.4 Synthesis of Amlodipine Besylate (Norvasc) 164
11.5 Synthesis of Azelnidipine (Calblock) 165
12 SECOND-GENERATION HMG-CoA REDUCTASE INHIBITORS 169Jeffrey A. Pfefferkorn
12.1 Introduction 170
12.2 Synthesis of Fluvastatin (Lescol) 171
12.3 Synthesis of Rosuvastatin (Crestor) 174
12.4 Synthesis of Pitavastatin (Livalo) 177
13 CHOLESTEROL ABSORPTION INHIBITORS: EZETIMIBE (ZETIA) 183Stuart B. Rosenblum
13.1 Introduction 183
13.2 Discovery Path to Ezetimibe 184
13.3 Synthesis of Ezetimibe (Zetia) 187
III CENTRAL NERVOUS SYSTEM DISEASES
14 DUAL SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS (SSNRIs) FOR DEPRESSION 199Marta Pineiro-Nunez
14.1 Introduction 200
14.2 Synthesis of Venlafaxine 203
14.3 Synthesis of Milnacipran 205
14.4 Synthesis of Duloxetine 207
15 GABAA RECEPTOR AGONISTS FOR INSOMNIA: ZOLPIDEM (AMBIEN), ZALEPLON (SONATA), ESZOPICLONE (ESTORRA, LUNESTA), AND INDIPLON 215Peter R. Guzzo
15.1 Introduction 216
15.2 Synthesis of Zolpidem 217
15.3 Synthesis of Zaleplon 219
15.4 Synthesis of Eszopiclone 220
15.5 Synthesis of Indiplon 221
16 Alpha2Delta LIGANDS: NEURONTIN (GABAPENTIN) AND LYRICA (PREGABALIN) 225Po-Wai Yuen
16.1 Introduction 225
16.2 Synthesis of Gabapentin 227
16.3 Synthesis of Pregabalin 234
17 APPROVED TREATMENTS FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER: AMPHETAMINE (ADDERALL), METHYLPHENIDATE (RITALIN), AND ATOMOXETINE (STRATERRA) 241David L. Gray
17.1 Introduction 242
17.2 Synthesis of Amphetamine 244
17.3 Synthesis of Methylphenidate 247
17.4 Synthesis of Atomoxetine 253
References 257
Index 261
