- Reviews on hot topics of interest in small molecule drug discovery heavily pursued by industrial research organizations
- Provides preclinical information in the context of chemical structures
- Knowledgeable section editors who evaluate invited reviews for scientific rigor
Annual Reports in Medicinal Chemistry provides timely and critical reviews of important topics in medicinal chemistry with an emphasis on emerging topics in the biological sciences that are expected to provide the basis for entirely new future therapies. Reviews on hot topics of interest in small molecule drug discovery heavily pursued by industrial research organizations Provides preclinical information in the context of chemical structures Knowledgeable section editors who evaluate invited reviews for scientific rigor
Front Cover 1
Annual Reports in Medicinal Chemistry 4
Copyright 5
Contents 6
Contributors 16
Preface 18
Personal Essays 20
Chapter One: A Personal Essay: My Experiences in the Pharmaceutical Industry 22
References 27
Chapter Two: Adventures in Medicinal Chemistry: A Career in Drug Discovery 30
Acknowledgments 40
References 40
Section 1: Central Nervous System Diseases 44
Chapter Three: Natural and Synthetic Neuroactive Steroid Modulators of GABAA and NMDA Receptors 46
1. Introduction 46
2. NAS Modulators of the GABAA Receptor 48
2.1. Endogenous NAS Modulators of the GABAA Receptor 50
2.2. Synthetic NAS Modulators of the GABAA Receptor 51
2.2.1. Anesthetics 51
2.2.2. Compounds Suitable for Nonanesthetic Indications 53
3. NAS Modulators of the NMDA Receptor 55
4. Conclusions 57
References 58
Chapter Four: Development of LRRK2 Kinase Inhibitors for Parkinson´s Disease 62
1. Introduction 62
2. LRRK2 Biology 63
3. Medicinal Chemistry 65
3.1. LRRK2 Patent Space Analysis 66
3.2. Chemical Scaffolds 67
3.2.1. Repurposed Kinase Inhibitors 69
3.2.2. First-Generation LRRK2-Focused Kinase Inhibitors 70
3.2.3. Second-Generation LRRK2-Focused Kinase Inhibitors 70
3.2.4. Third-Generation LRRK2-Focused Kinase Inhibitors 72
4. Preclinical Animal Models 73
5. Conclusions 74
References 74
Chapter Five: Stimulating Neurotrophin Receptors in the Treatment of Neurodegenerative Disorders 78
1. Introduction 78
2. NTs and NT Receptors-Structure and Function 79
3. Role of NTs and Their Receptors in Neurodegenerative Disorders 80
4. Pharmacological Activators of NT Receptors 81
4.1. Peptidic Activators 81
4.2. Small-Molecule Activators 82
5. Conclusion 90
References 90
Section 2: Cardiovascular and Metabolic Diseases 94
Chapter Six: Small-Molecule Modulators of GPR40 (FFA1) 96
1. Introduction 96
2. Recent Discoveries in GPR40 Biology 97
3. GPR40 Partial Agonists 98
3.1. TAK-875 98
3.2. AMG 837 99
3.3. LY2881835 100
4. GPR40 Full Agonists 101
5. Conclusions 103
References 104
Chapter Seven: Recent Advances in the Development of P2Y12 Receptor Antagonists as Antiplatelet Agents 106
1. Introduction 106
2. FDA-Approved P2Y12 Receptor Antagonists 107
2.1. Thienopyridines 108
2.2. ATP Analogs 109
3. New P2Y12 Receptor Antagonists 109
3.1. ATP Analogs 109
3.2. Thienopyridines 111
3.3. Miscellaneous Scaffolds 112
3.3.1. Phenylpyrazole Glutamic Acid Piperazines 112
3.3.2. 6-Aminonicotinates 113
4. Clinical Application 114
5. Conclusions 116
References 116
Chapter Eight: Current Approaches to the Treatment of Atrial Fibrillation 120
1. Introduction 120
2. Atrial-Selective Agents Versus Non-selective Agents 121
2.1. Current Standard of Care 121
2.2. Mechanism and Atrial-Specific Ion Channels 122
3. Clinical Updates 122
3.1. Non-selective Agents 122
3.2. Atrial-Selective Agents 123
3.2.1. IKur Inhibitors 123
3.2.2. IKAch Inhibitors 124
4. Preclincal Advances 124
4.1. IKur Inhibitors 124
4.1.1. Thienopyrimidines and Thienopyrazoles 124
4.1.2. Imidazolidinones 125
4.1.3. Indazole and Pyrrolopyrimidines 125
4.1.4. Phenylsulfonamides 126
4.1.5. Phenylcyclohexanes and gem-Dimethyl Isoindolinone 128
4.1.6. Benzodiazepines 128
4.2. IKAch Inhibitors 129
4.2.1. Benzamides 129
5. Conclusion 129
References 130
Section 3: Inflammation/Pulmonary/GI Diseases 134
Chapter Nine: Advances in the Discovery of Small-Molecule IRAK4 Inhibitors 136
1. Introduction 136
2. Rationale for Targeting IRAK4 in Inflammatory Diseases 137
2.1. TLR and IL-1R Signaling 137
2.2. Human IRAK4-Deficient Patients 137
2.3. Genetic Validation 138
2.4. TLR and IL-1-Targeted Therapies 138
2.5. IRAK4 and Cancer 139
3. IRAK4 Structure 139
4. Recent Medicinal Chemistry Efforts 140
4.1. Benzimidazoles 140
4.2. Thiazole, Pyridyl, and Oxazole Amides 142
4.3. Pyrazolo and Thiophene Fused Pyrimidine Amides 143
4.4. Pyridyl Amines 144
4.5. 6,5-Fused Tricyclic Thienopyrimidines and Related Heterocycles 145
4.6. Other Heterocyclic Cores 147
5. Conclusions 149
References 149
Chapter Ten: H4 Receptor Antagonists and Their Potential Therapeutic Applications 154
1. Introduction 154
1.1. Histamine Receptor Family 154
1.2. Expression and Function of the Histamine H4 Receptor 155
2. Antagonists of the H4 Receptor 155
2.1. Indole and Benzimidazole Amide Ligands 155
2.2. Dibenzodiazepine, Quinoxalinone, and Quinazoline Ligands 156
2.3. Pyrimidine-Based Ligands 157
3. Role of the Histamine H4 Receptor in Disease Models 163
3.1. Acute Inflammation and Inflammatory Pain 163
3.2. Rheumatoid Arthritis 163
3.3. Asthma 164
3.4. Pruritis 164
4. Clinical Development of H4 Receptor Antagonists 165
5. Conclusions 165
References 165
Chapter Eleven: Urate Crystal Deposition Disease and Gout-New Therapies for an Old Problem 170
1. Introduction 170
2. Therapeutics for Gout by Clinical Manifestation 172
2.1. Gout Flares 172
2.1.1. Nonsteroidal Anti-Inflammatory Drugs 173
2.1.2. Colchicine 173
2.1.3. Glucocorticoids 173
2.1.4. IL-1 Blockade 174
2.1.5. Phosphodiesterase-4 174
2.1.6. Anti-C5a Antibody 175
2.1.7. CXCR2 175
2.2. Hyperuricemia 175
2.2.1. Drugs Blocking Uric Acid Production 176
2.2.1.1. XO Inhibition 177
2.2.1.2. Purine Nucleoside Phosphorylase Inhibition 178
2.2.1.3. Concentrative Nucleoside Transporter Type 2 178
2.2.2. Drugs Increasing Uric Acid Excretion 179
2.2.3. Drugs Catalyzing Uric Acid Metabolism 181
3. Conclusions 181
References 182
Section 4: Oncology 184
Chapter Twelve: p53-MDM2 and MDMX Antagonists 186
1. Introduction 186
1.1. Importance of p53/MDM2/MDMX in Tumor Suppression (p53 Pathway Regulation) 187
1.2. The p53/MDM2/MDMX Interaction (Crystal Structures) 187
2. MDM2 Antagonists 188
2.1. Nutlin-Type Compounds 188
2.2. Imidazoles 189
2.3. Imidazothiazoles 190
2.4. Benzodiazepines 191
2.5. Spirooxindoles 192
2.6. Isoindolones 192
2.7. Indole-2-Carboxylic Acid Derivatives 193
2.8. Pyrrolidinones 194
2.9. Pyrrolidines 195
2.10. Isoquinolines and Piperidinones 196
2.11. Peptides 197
2.12. Miscellaneous Compounds 198
3. MDMX Antagonists 199
3.1. Imidazoles 199
3.2. Miscellaneous Compounds 200
4. Conclusion 202
References 203
Chapter Thirteen: Modulators of Atypical Protein Kinase C as Anticancer Agents 208
1. Introduction 208
1.1. Overview of Protein Kinase C Isoforms 208
2. Atypical Protein Kinase C Isoforms 209
2.1. aPKC Activation Mechanisms 209
2.2. aPKC Structure 210
2.3. aPKC Function 211
3. Disease Linkage of Atypical PKCs 212
3.1. Oncology 212
3.2. Metabolic Diseases 213
3.3. Other Indications 214
4. Non-ATP-Binding Site Inhibitors 215
4.1. PB1 Domain of aPKC (Gold Complexes) 215
4.2. C-terminal Lobe of the Catalytic Domain of aPKC 215
4.3. aPKC Pseudosubstrate Binding Site 216
4.4. Allosteric PIF-1 Domain Binding 217
4.5. Undefined Binding Modes 217
5. ATP-Binding Site Inhibitors 218
6. Conclusions 221
References 221
Section 5: Infectious Diseases 226
Chapter Fourteen: Advancement of Cell Wall Inhibitors in Mycobacterium tuberculosis 228
1. Introduction 228
2. Cell Wall Inhibitors 230
2.1. InhA 230
2.2. DprE1 232
2.3. MmpL3 233
2.4. Peptidoglycan Synthesis 235
2.5. Emerging Targets 236
3. Conclusions 236
References 237
Chapter Fifteen: Nucleosides and Nucleotides for the Treatment of Viral Diseases 240
1. Introduction 240
2. Human Immunodeficiency Virus 241
3. Hepatitis B Virus 247
4. Hepatitis C Virus 250
5. Dengue Virus 259
6. Conclusion 261
References 261
Chapter Sixteen: Advances in Inhibitors of Penicillin-Binding Proteins and ß-Lactamases as Antibacterial Agents 268
1. Introduction 268
2. PBP Inhibitors 269
2.1. ß-Lactam-Based Inhibitors 269
2.1.1. Cephems: Cephalosporins 270
2.1.2. Penems: Carbapenems 272
2.1.3. Monobactams 273
2.2. Non-ß-Lactam PBP Inhibitors 274
2.2.1. Covalent Inhibitors 274
2.2.2. Noncovalent Inhibitors 275
3. ß-Lactamase Inhibitors 276
3.1. Serine ß-Lactamase Inhibitors 276
3.1.1. DBO-Based BLIs 276
3.1.2. Boronic Acid-Based BLIs 279
3.2. Metallo-ß-Lactamase Inhibitors 279
3.2.1. Dicarboxylate Inhibitors 280
3.2.2. Thiolate-Based Inhibitors 281
3.2.3. Other Small Molecule Inhibitors 281
4. Conclusions and Outlook 282
References 282
Section 6: Topics in Biology 286
Chapter Seventeen: Tumor Microenvironment as Target in Cancer Therapy 288
1. Introduction 288
2. Cancer-Promoting Enzymes and Inhibitors 289
2.1. MMPs and Their Inhibitors 289
2.1.1. Matrix Metalloproteinase-2 and Its Inhibitors 290
2.1.2. Matrix Metalloproteinase-12 and Its Inhibitors 291
2.1.3. Matrix Metalloproteinase-13 and Its Inhibitors 292
2.1.4. Tumor Necrosis Factor--Converting Enzyme and Its Inhibitors 293
2.2. Regulation of Microenvironment pH 294
2.2.1. H+ Pumps and Transporters 294
2.2.2. Tumor-Associated Carbonic Anhydrases 294
2.3. Ectonucleotidases 296
2.3.1. Autotaxin 296
2.3.2. CD73 297
2.3.3. CD39 297
2.3.4. Miscellaneous 298
3. Carbamoylphosphonates: Inhibitors of Extracellular Zinc-Enzymes 298
4. Conclusions and Outlook 300
Acknowledgments 300
References 301
Chapter Eighteen: Novel Screening Paradigms for the Identification of Allosteric Modulators and/or Biased Ligands for Cha... 304
1. Introduction 305
2. Allosteric Modulators 306
2.1. AM Screening: Challenges 306
2.2. AM Screening: Illustrative Examples 307
2.3. AM Screening: Novel Approaches 309
3. Biased Ligands 310
3.1. BL Identification: Characteristics 310
3.2. BL Identification: Illustrative Examples 311
3.3. BL Identification: Novel Approaches 313
4. Ab Discovery as Novel AMs/BLs 315
5. Conclusions 317
References 317
Chapter Nineteen: Mer Receptor Tyrosine Kinase: Therapeutic Opportunities in Oncology, Virology, and Cardiovascular Indic... 320
1. Introduction 321
2. Mer Biological Function and Therapeutic Opportunities 322
2.1. Mer´s Role in Macrophages, Natural Killer, and Dendritic Cells 322
2.2. Aberrant Expression of Mer in Hematological and Solid Tumors: A Dual Target for Anticancer Effects 323
2.3. The Role of TAM Family Kinases in Viral Immune Avoidance 324
2.4. Mer´s Role in Coagulation: An Anticoagulation Target with Minimal Bleeding Liabilities 325
3. Small Molecule Mer Inhibitors 325
3.1. Current Clinical Agents with TAM Family Activity 326
3.2. Novel Mer Inhibitors with Activity in In Vivo Models of Antitumor, Anticoagulation, and Antiviral Indications 326
4. Future Directions and Conclusions 329
References 329
Section 7: Topics in Drug Design and Discovery 334
Chapter Twenty: Disease-Modifying Agents for the Treatment of Cystic Fibrosis 336
1. Introduction 337
1.1. Classes of CFTR Mutations 337
1.2. Cellular Assays 338
1.3. Other Strategies to Correct Airway Surface Liquid Defects 338
2. Treating Class I Defects 339
2.1. Ataluren (PTC124, 1) 339
2.2. NB124 (2) 339
3. Treating Class II Defects (Correctors) 340
3.1. VX-809 (Lumacaftor, 3) 340
3.2. VX-661 (4) 341
3.3. FDL169 341
3.4. 407882 (5) 341
3.5. Matrine (6) 341
3.6. Apoptozole (7) 342
3.7. Latonduine A (8) 342
3.8. Kinase Inhibitors 342
3.9. Other Correctors 342
4. Treating Class III Defects (Potentiators) 343
4.1. VX-770 (Ivacaftor, 12) 343
4.2. RP193 343
4.3. GLPG1837 343
4.4. Other Potentiators 344
5. Compounds with Dual Activity 344
5.1. N6022 (15) and N91115 344
5.2. CoPo-22 (16) 345
5.3. Hyalout4 (17) 345
5.4. Other Compounds with Dual Activity 345
6. Conclusions 345
References 346
Chapter Twenty-One: Advancements in Stapled Peptide Drug Discovery and Development 350
1. Introduction 350
2. Beneficial Effects Attributed to the Hydrocarbon Staple 351
2.1. Enhancing Pharmacokinetic Properties 352
2.2. Generating Cell Permeability 353
2.3. Improved Target Affinity and Target Specificity 354
3. Drug Discovery: Preclinical Research 355
3.1. BCL-2 Pathway Modulators 355
3.2. Wnt Pathway Modulators 357
3.3. HIV Inhibitors 358
4. Drug Development and P53 Reactivation 359
4.1. From In Vitro to In Vivo Proof of Concept 359
4.2. Advantages with SPs over Small Molecules 361
5. Concluding Remarks 361
References 362
Chapter Twenty-Two: Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development 366
1. Introduction 366
2. Identification of CYP-Modified Natural Products as Drug Leads 367
2.1. Antineoplastic Agents 367
2.2. Antiprotozoal Agents 368
2.3. Antifungal Agents 369
3. Identification of Pharmacologically Active Metabolites of Known Drugs 370
3.1. Statin Metabolites 371
3.2. Antibiotics 371
3.3. Antidepressants 373
3.4. Antihistamines 374
3.5. Muscarinic Antagonists 374
3.6. Antineoplastic Agents 375
4. Future Directions and Conclusions 375
Acknowledgments 376
References 376
Section 8: Case Histories and NCEs 380
Chapter Twenty-Three: Case History: ForxigaTM (Dapagliflozin), a Potent Selective SGLT2 Inhibitor for Treatment of Diabetes 382
1. Introduction 382
2. Renal Recovery of Glucose 383
3. O-Glucoside SGLT2 Inhibitors 385
4. C-Aryl Glucoside SGLT2 Inhibitors 390
5. Synthesis of Dapagliflozin 395
6. Preclinical Profiling Studies with Dapagliflozin 396
7. Clinical Studies with Dapagliflozin 398
8. Conclusion 399
References 400
Chapter Twenty-Four: Case History: Kalydeco® (VX-770, Ivacaftor), a CFTR Potentiator for the Treatment of Patients with C... 402
1. Introduction 402
2. CFTR as a Drug Discovery Target 404
3. The Discovery of CFTR Potentiators 405
4. Medicinal Chemistry Efforts Culminating in Ivacaftor 405
4.1. Hit-to-Lead Efforts 406
4.2. Reducing the Planarity of VRT-715 407
4.3. Final Compound Selection 409
5. Preclinical Properties of Ivacaftor 410
6. Formulation Development 411
7. Clinical Studies 414
8. Conclusion 415
References 416
Chapter Twenty-Five: Case History: Xeljanz (Tofacitinib Citrate), a First-in-Class Janus Kinase Inhibitor for the Treatme... 418
1. Introduction 418
2. Rationale for Targeting the JAK Enzymes 420
3. Medicinal Chemistry Efforts Culminating in the Identification of Tofacitinib15 422
3.1. Lead Identification: High-Throughput Screening 423
3.2. Early Structure-Activity Relationships: Developing a Pharmacophore Model 424
3.3. Informing Headgroup Structure: High-Speed Analoging and Natural Products 425
3.4. Optimizing Property Space and ADME 427
4. Selectivity and Pharmacology of Tofacitinib 429
5. Preclinical Properties of Tofacitinib 431
6. Clinical Properties of Tofacitinib 432
7. Conclusions 433
Acknowledgments 433
References 433
Chapter Twenty-Six: New Chemical Entities Entering Phase III Trials in 2013 436
Selection Criteria 436
Facts and Figures 437
References 453
Chapter Twenty-Seven: To Market, To Market-2013 456
Overview 457
1. Acotiamide (Dyspepsia)11-17 466
2. Ado-Trastuzumab Emtansine (Anticancer)18-22 468
3. Afatinib (Anticancer)23-29 470
4. Canagliflozin (Antidiabetic)30-42 472
5. Cetilistat (Antiobesity)43-52 473
6. Cobicistat (Antiviral, Pharmacokinetic Enhancer)53-59 475
7. Dabrafenib (Anticancer)60-65 477
8. Dimethyl Fumarate (Multiple Sclerosis)66-80 479
9. Dolutegravir (Antiviral)81-91 480
10. Efinaconazole (Antifungal)92-98 482
11. Elvitegravir (Antiviral)99-108 484
12. Ibrutinib (Anticancer)109-114 485
13. Istradefylline (Parkinson´s Disease)115-122 487
14. Lixisenatide (Antidiabetic)123-131 489
15. Macitentan (Antihypertensive)132-138 491
16. Metreleptin (Lipodystrophy)139-150 493
17. Mipomersen (Antihypercholesteremic)151-158 495
18. Obinutuzumab (Anticancer)159-164 497
19. Olodaterol (Chronic Obstructive Pulmonary Disease)165-174 499
20. Ospemifene (Dyspareunia)175-181 501
21. Pomalidomide (Anticancer)182-195 503
22. Riociguat (Pulmonary Hypertension)196-203 505
23. Saroglitazar (Antidiabetic)204-212 507
24. Simeprevir (Antiviral)214-223 508
25. Sofosbuvir (Antiviral)224-235 511
26. Trametinib (Anticancer)236-242 513
27. Vortioxetine (Antidepressant)243-252 515
References 517
Keyword Index, Volume 49 528
Cumulative Chapter Titles Keyword Index, Volume 1 - 49 538
Cumulative NCE Introduction Index, 1983-2013 562
Cumulative NCE Introduction Index, 1983-2013 (By Indication) 588
Color Plate 614
A Personal Essay
My Experiences in the Pharmaceutical Industry
John J. Baldwin Gwynedd Valley, PA, USA
I am a chemist, a medicinal chemist, born in Wilmington, Delaware, the cradle of the U.S. chemical industry, the home of DuPont and its postmonopoly offspring, Hercules and Atlas. Wilmington borders on three rivers, the Delaware, the Brandywine, and the Christiana. The fourth connecting side was dominated by the three research centers of DuPont and its spin-offs.
Like most budding scientists, I had the obligatory chemistry sets. My dream was to work someday in those beautiful research centers in the Wilmington suburbs, surrounded by parks and golf courses. (Of course there were the other dreams, maybe being a Bishop or riding on horseback into the sunset with imaginary cowboy friends, but that's another story.)
When choosing science as a career, it is important to develop a strong foundation in mathematics, languages, biology, chemistry, and physics. It is also important to immerse yourself in a motivating and competitive environment. A strong work ethic is critical. When I attended the University of Delaware as a chemistry major, I carried a full schedule each year while working 24 h a week in the analytical lab at Halby Chemical. My interest in biology was evident in my course selection: biology, physiology, and psychology. My thesis, under John Wriston, focused on the possible fate of one-carbon fragments produced during metabolism. At the University of Delaware, I felt that I had prepared myself to dig deeper into the biological sciences in graduate school. Work hard; study harder.
For graduate school, I chose the University of Minnesota and was fortunate to receive a teaching fellowship. I majored in Organic Chemistry and minored in Biochemistry, which was structured within the Medical School. My mentor in synthetic chemistry was Lee Smith, a member of the National Academy of Science and an expert in quinone chemistry, especially as it related to vitamin E and coenzyme Q. My minor in Biochemistry required 2 years of heavy course work. My mentor here was Paul Boyer, the Nobel Prize winner. Working with both of these men was a great experience. My research in synthetic organic chemistry and the courses within the Medical School prepared me well for a future in drug discovery. Work hard; study harder.
After saying farewell to graduate school in 1960, I joined the Medicinal Chemistry Department of Merck and Company's West Point, Pennsylvania, laboratory. The company, then known as Merck Sharp & Dohme, had formed through a merger following the discovery at Sharp & Dohme of hydrochlorothiazide, a game changing medication for the treatment of hypertension and, in my thinking, the beginning of modern hypothesis-driven drug discovery.
The Merck laboratory in Rahway, New Jersey, focused on antibiotic chemistry, which had evolved from the penicillin program; steroids, which grew out of cortisone synthesis; and vitamins, stemming from their fine chemicals background. The West Point laboratory was devoted to cardiovascular and CNS diseases, antisecretory/antiulcer agents, atherosclerotic disease, and antiviral agents.
I became involved in many of the West Point programs, including loop diuretics, xanthine oxidase inhibitors, beta adrenergic blockers, vasodilators, dopamine agents for Parkinson's disease, antivirals, and carbonic anhydrase inhibitors for glaucoma. Learning pharmacology was never ending in the Merck environment. Work hard; study harder.
The areas that were especially attractive to me were the mechanistic approach to drug discovery and understanding the biochemistry of disease, using computationally intensive predictive methods and X-ray crystallography of ligand–protein complexes. From this work came Edecrin, Crixivan, Trusopt, Cosopt, and the antiulcer agent famotidine (Pepcid), which I identified in the patent literature and championed through the Merck system. The work, that led to the first topically available carbonic anhydrase inhibitor, dorzolamide (Trusopt), has been described in terms of its design, computational understanding, conformational analysis, and X-ray crystallographic details of the enzyme/ligand structure.1 This integration of disciplines established a powerful approach to drug design that I repeated in the discovery of the HIV protease inhibitors at Merck and the renin inhibitors at Vitae.
A compound that created excitement within research but failed to reach the market was the topically penetrating, direct-acting dopamine agonist for Parkinson's disease. The compound was administered via patch and effectively controlled symptoms. However, as sometimes happens, the Research Division could not convince the Clinical/Marketing Organization to continue with clinical trials.
In 1993, Merck began to prepare for the twenty-first century and the predicted patent cliff which lay ahead. One step was to decrease staff through a retirement incentive plan. Cut-backs not only pose difficult decisions for management but impose difficult decisions on the people affected as well. Such actions by Merck and other companies marked the disappearance of the lifelong commitment of an employee to a single company and the belief that the commitment of the company to this contract would also be honored. A new era in the company/employee relationship had begun. This new reality became even more apparent over the past decade, and it must be considered by professionals and students alike as they make choices about employment. I adjusted to this apparent evolutionary change by deciding not only to take Merck's offer but to start a new company, Pharmacopeia, which was based on cutting-edge technology not being practiced in Big Pharma. Jack Chabala, also from Merck, and Larry Bock of Avalon Ventures joined me in launching the new company around encoded combinatorial chemistry and high-throughput screening. This technology played a key role in exploiting the genomic revolution and the target-specific approach to drug discovery.
Pharmacopeia perfected the synthesis of encoded solid-phase combinational libraries, which allowed the preparation and screening of large compound collections across numerous in vitro assays. These screening collections, built on a common theme, would be followed by smaller libraries focused on the bioactive lead.
Within a few years, the approach was adopted by all pharmaceutical companies, and the ability to generate large screening collections became a technology that was required within every drug discovery organization. The only advantage that Pharmacopeia had in selling what had become a commodity was price and its experience in drug discovery. One obvious solution to the price issue was to move compound production to a lower-cost environment. After first looking into a joint venture possibility in China and finding no interest at Pharmacopeia, I, along with one of our founding scientists, Ge Li, and three others decided to finance a new company, WuXi Pharma Tech. This Contract Research Organization grew rapidly and is the largest company in China servicing the research needs of the U.S. and European pharmaceutical industries.
With WuXi Pharma Tech successfully listed on the New York Stock Exchange, it was time to start something new. That new endeavor was Concurrent Pharma, later Vitae Pharma, which was based on computational methods from Eugene Shakhnovich's laboratory at Harvard. The method defines in detail a ligand–protein complex that was constructed in silico, fragment by fragment, along the surface of the target. The computational exercise was followed by chemical synthesis of the predicted ligand and appropriate in vitro testing. The predicted complex then could be verified by X-ray crystallography. We found a problem that was ideally suited to test the technology among the aspartic acid proteases, renin and beta-secretase. The approach produced novel, nonpeptidic, and bioavailable inhibitors of both enzymes. A similar approach was used to find inhibitors of 11-beta-hydroxysteroid dehydrogenase, a flexible enzyme that offered an additional challenge. This de novo design strategy holds great promise for the future, especially for the virtual company that lacks the internal architecture of Big Pharma.
During this evolutionary period of Vitae Pharma, the drug-discovery capability in China continued to develop such that the time seemed right for a new company not only capable of research support but also of drug discovery, development, toxicology, registration, and human clinical trials, each component present in a virtual organization. So, Bob Nelson of Arch Ventures and I decided to start a new company, Hua Medicine. This China-centric company will move its first drug candidate into human Phase I clinical trials this year, 2013.
Looking back to the start of the biotech era, it is clear that start-up companies continue to be a high-risk exercise. Whether the company is large or small, it still takes years and over a billion dollars to discover and develop a New Chemical Entity (NCE). This forces the small biotech firm to be in a constant search for financing and for a viable exit strategy.
Recent years have not been easy ones, especially for the major pharmaceutical companies, which faced a slowing rate of discovery, major products going “off patent” into the generic class, higher R&D costs, and longer approval times. To combat this, a range of new survival strategies has been developed and adopted,2,3 including a series of mega-mergers with the resulting cut-back in employment....
| Erscheint lt. Verlag | 1.10.2014 |
|---|---|
| Mitarbeit |
Herausgeber (Serie): Manoj C Desai |
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Allgemeines / Lexika |
| Medizin / Pharmazie ► Gesundheitsfachberufe | |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie | |
| Naturwissenschaften ► Chemie ► Organische Chemie | |
| ISBN-10 | 0-12-800372-3 / 0128003723 |
| ISBN-13 | 978-0-12-800372-5 / 9780128003725 |
| Haben Sie eine Frage zum Produkt? |
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EPUB (Adobe DRM)Größe: 49,5 MB
Kopierschutz: Adobe-DRM
Adobe-DRM ist ein Kopierschutz, der das eBook vor Mißbrauch schützen soll. Dabei wird das eBook bereits beim Download auf Ihre persönliche Adobe-ID autorisiert. Lesen können Sie das eBook dann nur auf den Geräten, welche ebenfalls auf Ihre Adobe-ID registriert sind.
Details zum Adobe-DRM
Dateiformat: EPUB (Electronic Publication)
EPUB ist ein offener Standard für eBooks und eignet sich besonders zur Darstellung von Belletristik und Sachbüchern. Der Fließtext wird dynamisch an die Display- und Schriftgröße angepasst. Auch für mobile Lesegeräte ist EPUB daher gut geeignet.
Systemvoraussetzungen:
PC/Mac: Mit einem PC oder Mac können Sie dieses eBook lesen. Sie benötigen eine
eReader: Dieses eBook kann mit (fast) allen eBook-Readern gelesen werden. Mit dem amazon-Kindle ist es aber nicht kompatibel.
Smartphone/Tablet: Egal ob Apple oder Android, dieses eBook können Sie lesen. Sie benötigen eine
Geräteliste und zusätzliche Hinweise
Buying eBooks from abroad
For tax law reasons we can sell eBooks just within Germany and Switzerland. Regrettably we cannot fulfill eBook-orders from other countries.
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