Real World Drug Discovery: A Chemist's Guide to Biotech and Pharmaceutical Research

Real World Drug Discovery A Chemist\'s Guide to Biotech and Pharmaceutical Research......Page 4
Copyright Page......Page 5
Table of Contents......Page 8
Preface......Page 13
Acknowledgements......Page 17
About the Author......Page 19
1.1 Introduction......Page 20
1.2.1 Pharma Roots......Page 21
1.2.2 Biotech is Born......Page 25
1.2.3 The Genomics Revolution......Page 28
1.3 Current Economics—Problems......Page 32
1.3.1 Cost of Drug Development......Page 33
1.3.2 The Productivity Gap......Page 35
1.3.3 Market Withdrawals......Page 38
1.3.4 Generic Competition......Page 40
1.4.1 Pharma Profits and Market Expansion......Page 45
1.4.2 Mergers and Acquisitions......Page 47
1.4.3 Biotech Clinical Candidates to Pharma......Page 48
1.4.4 Academic Contributions......Page 50
1.4.5 Global Outsourcing......Page 51
1.4.6 Blockbusters and Orphan Drugs......Page 58
1.4.7 Repurposing......Page 59
1.4.8 Chiral Switching......Page 61
1.4.9 Combination Therapeutics......Page 63
1.4.10 Reformulation......Page 64
1.5 Summary......Page 65
2.2.1 R&D Minus R......Page 72
2.2.2 D Plus R......Page 75
2.2.3 Smaller is Better......Page 77
2.2.5 Pricing Pressures and Price Controls......Page 79
2.3.1 Translational Research......Page 84
2.3.2 The Standard Biotech Model......Page 87
2.3.3 \"Is it a project or a company?\"......Page 91
2.3.4 Leaner, Meaner Start-ups......Page 93
2.3.5 Biotech Alternatives......Page 94
2.4.1 S-Curves and Expectations......Page 99
2.4.2 Genomics Redux......Page 104
2.4.3 Personalized Medicine......Page 107
2.4.4 Pharmacogenomics......Page 108
2.4.5 Other \"Omics\"......Page 117
2.4.6 The Adoption of Personalized Medicine......Page 121
2.5 Summary......Page 123
3.1.1 The Value of New Ideas......Page 132
3.1.2 Patents......Page 137
3.2.1 Consultants......Page 151
3.2.2 Academic or Government Research Agreements......Page 155
3.2.3 Big Company–Small Company Collaborations......Page 157
3.3.1 Target Identification......Page 160
3.3.3 Lead Optimization......Page 162
3.3.4 Preclinical......Page 163
3.3.5 Stages in Clinical Development......Page 165
3.3.6 What are the Odds?......Page 166
4.1 Introduction......Page 170
4.2.1 The Project Goal......Page 171
4.2.2 Project Team Organization......Page 174
4.2.3 Project Team Meetings......Page 183
4.3.1 Summing Up.........Page 190
4.3.2 Is it Really Best?......Page 191
4.3.3 The Benefits......Page 192
5.1 Introduction......Page 194
5.2 Established Targets......Page 195
5.3 Established \"Tough Targets\"......Page 201
5.4.1 Identifying New Targets......Page 202
5.4.2 Target Validation......Page 204
5.4.3 Working on Novel Target-Directed Projects......Page 214
5.5.1 Phenotype Screening Versus Target Screening......Page 219
5.5.2 Elucidation of Phenotype-Derived Targets......Page 225
5.6 In Conclusion......Page 231
6.2 Definitions......Page 237
6.3 Groups Involved in Hit-to-Lead......Page 239
6.4.1 History......Page 240
6.4.2 Myths and Truths about HTS......Page 241
6.5.1 Random or Non-Directed Methods......Page 259
6.5.2 Screening of Synthetic Compound Collections......Page 260
6.5.3 Screening of Combinatorial Diversity Libraries......Page 263
6.5.4 Fragment Screening......Page 267
6.5.5 Screening of Natural Products and DOS Libraries......Page 276
6.5.6 Directed or Knowledge-Based Methods......Page 281
7.1 What Now?......Page 299
7.2.1 Competition and Allostery......Page 300
7.2.2 Irreversibility......Page 304
7.2.3 Slow Off-Rate Compounds......Page 305
7.2.4 Why Mechanism Matters......Page 307
7.3.1 What is It?......Page 308
7.3.2 Predicting Druglikeness......Page 309
7.4 Multidimensional Optimization......Page 312
7.5 Lead Optimization Versus HTL......Page 314
7.6.1 Definition, History, and Goals......Page 315
7.6.2 Potential Limitations......Page 318
7.6.3 Examples......Page 321
7.6.4 Working with Modelers......Page 326
7.6.5 Conclusions......Page 327
8.2.1 What, Why, and How Much?......Page 332
8.2.2 Species Specificity......Page 334
8.3.1 Selectivity ... Not!......Page 336
8.3.2 Antitargets......Page 339
8.4.1 Bioisosteres, Group, and Atom Replacements......Page 342
8.4.2 Scaffold Hopping, Morphing, and Grafting......Page 347
8.4.3 Cyclization and Ring Opening......Page 350
8.4.4 Other Methods......Page 352
8.5.2 Problems Resulting from Poor Solubility......Page 354
8.5.3 Improving Solubility......Page 356
8.6.1 Definitions and Importance......Page 359
8.6.2 Common Types of Instability......Page 360
9.1.1 Definitions......Page 372
9.1.2 A Closer Look at Intestinal Absorption......Page 374
9.1.3 Models of Cell Permeability and Absorption......Page 377
9.1.4 Improving Cell Permeability and Absorption......Page 388
9.2 Metabolic Stability......Page 393
9.2.1 Common Metabolic Transformations......Page 394
9.2.2 Assessing Metabolic Stability......Page 401
9.2.3 Improving Metabolic Stability......Page 404
9.3.1 Is It Important?......Page 411
9.3.2 Measuring Plasma Protein Binding......Page 415
9.3.3 Minimizing Plasma Protein Binding......Page 417
9.4.1 Structure and Function......Page 420
9.4.2 Types of P-gp Interactions......Page 423
9.4.3 Measuring P-gp Interactions......Page 424
9.4.4 Reducing P-gp Interactions......Page 427
9.5.1 Introduction......Page 430
9.5.2 Understanding and Overcoming Poor Oral Bioavailability......Page 432
9.5.3 Things to Keep in Mind......Page 437
10.1.1 Importance......Page 449
10.1.2 Types of CYP Inhibition......Page 451
10.1.3 CYP Inhibition Assays......Page 453
10.1.4 Common Structural Features of CYP Inhibitors......Page 457
10.1.5 Ways to Reduce CYP Inhibition......Page 460
10.2 CYP Induction......Page 464
10.3.1 Introduction......Page 469
10.3.2 In Vitro Assays......Page 470
10.3.3 Models of hERG binding......Page 471
10.3.4 Reducing hERG Interactions......Page 473
10.4.1 Background......Page 476
10.4.2 Structural Aspects......Page 479
11.1.1 What Do Employers Want?......Page 488
11.1.2 What Should a Candidate Look For?......Page 493
11.2.1 Evaluations......Page 501
11.2.2 Promotions......Page 503
11.3 The Long Haul: Perspectives......Page 504
11.3.1 Job and Industry Evolution......Page 505
11.3.2 The Evolution of a Research Career......Page 506
11.3.3 Frustration......Page 508
11.3.4 Hope......Page 509
Appendix Best-Selling Small Molecule Single Agent Prescription Drugs: \"The Periodic Table of Drugs 2006\"......Page 514
Notes......Page 517
Index......Page 518