Accounts in Drug Discovery: Case Studies in Medicinal Chemistry (RSC Drug Discovery Series, Volume 4)

Cover......Page 1
Accounts in Drug Discovery: Case Studies in Medicinal Chemistry......Page 4
ISBN 978-1-84973-126-3......Page 5
Foreword......Page 6
Preface......Page 8
Contents......Page 10
1.1 Introduction......Page 18
1.2 Modulation of GLP-1 in the Treatment of Diabetes......Page 19
1.3 Dipeptidyl Peptidase-4 as a Target for Diabetes Treatment......Page 20
1.4 Early Inhibitors of DPP4......Page 21
1.5 Design of BMS’s DPP4 Medicinal Chemistry Program......Page 23
1.6 Design of Cyclopropyl-fused Nitrilo-pyrrolidines......Page 25
1.7 SAR Optimization Leading to the Discovery of Saxagliptin......Page 27
1.8 Binding of Saxagliptin to Human DPP4: A Slow Tight-binding Inhibitor......Page 29
1.9 Chemical Stability of Saxagliptin and Analogs......Page 31
1.10 In vivo Efficacy of Saxagliptin
......Page 32
1.11 Peptidase Selectivity of Saxagliptin......Page 33
1.12 Synthesis of Saxagliptin......Page 34
1.13 Saxagliptin Development......Page 35
1.14 Summary......Page 36
References......Page 37
2.1 Introduction......Page 42
2.2 Mechanism of Platelet Activation......Page 43
2.4 Thrombin Receptor (Protease-activated Receptor-1) Antagonists as Promising Antiplatelet Agents with Improved Safety Margin......Page 46
2.5 Conclusion......Page 63
References......Page 64
3.1 Introduction and Target Background......Page 68
3.2 Hit Generation and Hit-to-lead Strategies......Page 71
3.3 Lead Optimization and Discovery of Piragliatin......Page 77
References......Page 85
4.1 Targeting the IGF-1R/IR Pathway for the Discovery of Anti-tumor Agents......Page 88
4.2 IGF-1R/IR Inhibitors as Anchors for Combinatorial Anti-cancer Drug Strategies......Page 90
4.4 Synthetic Routes to Imidazopyrazine-derived IGF-1R Inhibitors......Page 91
4.5 Series I: Benzyloxyphenyl-derived Imidazopyrazine IGF-1R Inhibitors......Page 92
4.6 Series II: Quinolinyl-derived Imidazopyrazine IGF-1R Inhibitors......Page 97
4.7 Synthesis of OSI-906......Page 103
4.8 OSI-906: Biochemical and Cellular IGF-1R Activity......Page 105
4.9 OSI-906: Selectivity Profile......Page 107
4.11 OSI-906: Pharmacokinetic Properties......Page 111
4.12 OSI-906: Antitumor Effects......Page 113
4.13 OSI-906: Pharmacokinetic/Pharmacodynamic Correlation......Page 114
4.15 Summary......Page 115
References......Page 116
5.1 Acute Myeloid Leukemia......Page 120
5.3 The Calicheamicins......Page 121
5.4 The Original Anti-CD33 Conjugate......Page 123
5.5 Conjugate Redesign......Page 124
5.6 Pharmacokinetic and Toxicology Studies......Page 129
5.7 Clinical Trials......Page 130
5.9 Summary and Future Prospects......Page 131
References......Page 132
6.1 Introduction......Page 137
6.2 Bristol-Myers Squibb Approach......Page 138
6.3 Advanced Preclinical Leads......Page 141
6.4 Clinical Leads......Page 145
6.5 Conclusion......Page 155
References......Page 157
7.1 Introduction: SSRIs and Premature Ejaculation......Page 159
7.2 Targeting a Rapid Tmax, Short Half-life Agent......Page 160
7.3 Reducing Volume Starting from a Precedented SSRI Template......Page 162
7.4 Optimising an Inherently Lower Volume Template: Diphenyl Ethers......Page 168
7.5 Profile of Dapoxetine......Page 179
References......Page 180
8.1 Introduction......Page 183
8.2 X-Ray Crystallography and Structure-based Drug Design......Page 185
8.4 Hit and Lead Optimisation......Page 187
8.5 Conclusions......Page 197
References......Page 198
9.1 AIDS and HIV......Page 200
9.2 HIV Infection and the Choice to Target CCR5 Antagonism......Page 201
9.3 CC Chemokine Receptor 5......Page 202
9.4 Identifying Leads with Affinity for CCR5......Page 203
9.5 Defining Objectives and an Appropriate Screening Sequence......Page 204
9.6 Developing SAR......Page 206
9.7 Exploration of the Tropane Core......Page 208
9.9 Closing in on Maraviroc......Page 212
9.10 Profiling Maraviroc......Page 215
9.12 Results from the Clinic......Page 216
9.13 Resistance to Maraviroc......Page 218
9.14 Identifying Back-up Agents......Page 219
9.15 Other CCR5 Antagonists......Page 222
9.16 Conclusions......Page 224
References......Page 225
10.1 Introduction......Page 232
10.2 Discovery of the Novel Nucleoside Phosphonate GS-9148......Page 236
10.3 Amidate Prodrug Development to Identify GS-9131......Page 244
10.4 Conclusion......Page 252
References......Page 253
11.1 Introduction......Page 255
11.2 The Discovery of PSI-6130......Page 258
11.3 The Prodrug RG7128......Page 264
11.4 PSI-7851: a Nucleotide Prodrug of the 2'-F-2'-C-Methyl
Class of Nucleosides......Page 270
11.5 Summary......Page 279
References......Page 280
12.1 Introduction......Page 284
12.2 Medicinal Chemistry: Hit, Lead and Candidate Generation......Page 289
12.3 Pre-clinical and Clinical Pharmacokinetics of PF-184298......Page 297
Acknowledgements......Page 301
References......Page 302
13.1 Introduction......Page 304
13.2 Lead Identification......Page 306
13.4 Lead Optimization......Page 307
13.5 Phase I Clinical Data for AMG 517......Page 316
13.6 Approaches to Address the Hyperthermic Response......Page 319
13.7 Summary......Page 325
References......Page 328
14.1 Introduction......Page 333
14.2 Rapamycin: Structure and Biochemical Mechanism of Action......Page 334
14.3 Immunophilin Screening and Cell-based Approaches to Identify Candidates for Pre-clinical Evaluation......Page 337
14.4 Chemical Biology of ILS-920: Towards an Understanding of the Molecular Mechanism of Action......Page 342
14.5 Concluding Remarks......Page 344
References......Page 345
15.1 Introduction......Page 349
15.2 Identifying the Right Lead......Page 350
15.3 Pursuing the First Clinical Candidate by De.ning the Desired Properties to Deliver a High-Quality Molecule......Page 353
15.4 The Search for a Backup......Page 358
15.5 Clinical Results and Challenges......Page 364
15.6 Attempting to Overcome Clinical Toxicology Findings: Merging Novel Templates to Develop Additional Drug Candidates......Page 365
15.7 New Thoughts with Regard to Receptor Occupancy......Page 370
15.8 Conclusion......Page 373
References......Page 374
Subject Index......Page 380