Annual Reports in Medicinal Chemistry (eBook)

Front cover 1
Annual Reports in Medicinal Chemistry 4
Copyright page 5
Contents 6
Contributors 16
Preface 18
Part I: Central Nervous System Diseases 20
Chapter 1. Recent Advances in the Discovery of GSK-3 Inhibitors and a Perspective on their Utility for the Treatment of Alzheimer’s Disease 22
1. Introduction 23
2. Etiology of Alzheimer’s Disease 23
3. Principal Functions of GSK-3 24
4. Additional Neuroprotective Indications for GSK-3 Inhibition 27
5. Selective Functional Inhibition of GSK-3 27
6. GSK-3 Isoforms 28
7. SK-3 Crystal Structures 28
8. Challenges in the Development of Effective GSK-3 Inhibitors 29
9. Advances in GSK-3 Inhibitors 30
10. Conclusion 42
References 42
Chapter 2. Advancements in the Development of Nitric Oxide Synthase Inhibitors 46
1. Introduction 46
2. NOS - Structure and Function 47
3. Selective NOS Inhibitors 52
4. Clinical Findings with NOS Inhibitors 60
5. Future Directions - Dual Action NOS Inhibitors 62
6. Conclusions 65
References 66
Chapter 3. Small-Molecule Protein-Protein Interaction Inhibitors as Therapeutic Agents for Neurodegenerative Diseases: Recent Progress and Future Directions 70
1. Introduction 71
2. Abeta Aggregation and Oligomers in Alzheimer’s Disease 72
3. Tau Aggregation in Alzheimer’s Disease 77
4. alpha-Synuclein Aggregation in Parkinson’s Disease 82
5. Conclusion 84
References 85
Chapter 4. Case History: Chantixtrade/Champixtrade (Varenicline Tartrate), a Nicotinic Acetylcholine Receptor Partial Agonist as a Smoking Cessation Aid 90
1. Introduction 91
2. Partial Agonists at Nicotinic ACh Receptors 93
3. The Search for Partial Agonists: Cytisine as a Key Starting Point 96
4. Semi-Synthetic Analogs of Cytisine 99
5. Cytisine Synthesis and Early Template Expansion 103
6. Discovery of the Bicyclic Benzazepine Core 106
7. Fused Bicyclic Benzazepines 111
8. In vivo Efficacy of Partial Agonists 112
9. Properties of Varenicline 114
10. Clinical Studies 117
11. Conclusions 117
References 118
Part II: Cardiovascular and Metabolic Diseases 122
Chapter 5. Case History on Tekturnareg/Rasilezreg (Aliskiren), a Highly Efficacious Direct Oral Renin Inhibitor as a New Therapy for Hypertension 124
1. Introduction 125
2. Rationale for the Use of Direct Renin Inhibitors 125
3. Pre-Clinical Models to Study Direct Renin Inhibitors 126
4. Medicinal Chemistry Evolution - The Early Renin Inhibitor Program at Ciba-Geigy 127
5. First Convergent and Scalable Synthesis Development 140
6. Pre-Clinical Properties of Aliskiren 141
7. Effects of Aliskiren in Disease Models 142
8. Clinical Studies with Aliskiren 142
9. Conclusions 143
References 143
Chapter 6. Advances in Vasopressin Receptor Agonists and Antagonists 148
1. Introduction 149
2. V1a Receptor Antagonists 150
3. V1b Receptor Antagonists 153
4. V2 Receptor Agonists 158
5. V2 Receptor Antagonists 159
6. Dual V1a-V2 Receptor Antagonists 160
7. Summary 162
References 163
Chapter 7. The Emergence of GPR119 Agonists as Anti-Diabetic Agents 168
1. Introduction 168
2. Discovery and Characteristics of GPR119 169
3. The Biology of GPR119 170
4. GPR119 Agonists: Medicinal Chemistry 173
5. Clinical Trial Status and Future Prospects 185
References 186
Chapter 8. Non-Peptide Ligands for the Gonadotropin Receptors 190
1. Introduction 190
2. Non-Peptide Small Molecule Gonadotropin Receptor Ligands 192
3. Therapeutic Indications and Clinical Findings 201
4. Conclusions and Future Prospects 203
References 204
Chapter 9. Recent Advances in Coagulation Serine Protease Inhibitors 208
1. Introduction 208
2. Factor Xa Inhibitors 209
3. Thrombin Inhibitors 214
4. Factor VIIa/TF Inhibitors 218
5. Factor IXa and XIa Inhibitors 220
6. Conclusions 222
References 222
Part III: Inflammation/Pulmonary/GI 228
Chapter 10. Advances in the Discovery of Anti-Inflammatory FMS Inhibitors 230
1. Introduction 230
2. Recent FMS Inhibitors 234
3. Conclusion 241
References 241
Chapter 11. Recent Advances in the Discovery of CB2 Selective Agonists 246
1. Introduction 246
2. Evaluation of CB2 Agonists In Preclinical Models 247
3. Medicinal Chemistry 251
4. Clinical Trials Status 260
5. Conclusions 261
References 262
Chapter 12. Advances in the Discovery of Small Molecule JAK3 Inhibitors 266
1. Introduction 266
2. Rationale for Selective Targeting of JAK3 in Inflammatory Diseases 267
3. Clinical Trials and Supporting Preclinical Data 269
4. Challenges in Designing Selective JAK3 Inhibitors 272
Recent Medicinal Chemistry Efforts 274
6. Conclusions 280
References 280
Chapter 13. Recent Advances in Adenosine Receptor (AR) Ligands in Pulmonary Diseases 284
1. Introduction 284
2. A1 Adenosine Receptor Antagonists: L-97-1, BG-9928, FK-838, and WRC-0571 285
3. A2A Adenosine Receptor Agonists: CGS-21680, UK-371104, and GW-328276 287
4. A2B Adenosine Receptor Antagonists: CVT-6883, MRE 2029-F20, LAS-38096, and OSIP-339391 289
5. A3 Adenosine Receptor Antagonists: MRS-1523, KF-26777, and MRE-3008-F20 291
6. Summary 293
References 294
Part IV: Oncology 298
Chapter 14. Recent Progress in the Development of Small Molecule Inhibitors of Insulin-Like Growth Factor-1 Receptor Kinase 300
1. Introduction 300
2. IGF-1R Signaling 302
3. ATP-Competitive Inhibitors 303
4. Non ATP-Competitive Inhibitors 312
5. Conclusions 314
References 315
Chapter 15. Case History: Discovery of Ixabepilone (IXEMPRATM), a First-in-Class Epothilone Analog for Treatment of Metastatic Breast Cancer 320
1. Introduction 321
2. Epothilone Natural Products 321
3. Approaches to Identify Drug Candidates 324
4. Preclinical Pharmacology 330
5. Clinical Results 334
6. Future Directions 336
7. Conclusions 338
References 338
Chapter 16. Hedgehog Signaling Pathway Inhibitors as Cancer Therapeutics 342
1. Introduction 342
2. Mechanism of Hedgehog Pathway Signaling 343
3. Inhibitors of the Hedgehog Pathway 344
4. Hedgehog Inhibitors in Clinical Trials 351
5. Conclusions 352
References 353
Chapter 17. Emerging Therapies Based on Inhibitors of Phosphatidyl-Inositol-3-Kinases 358
1. Introduction 358
2. Inhibitors of PI3Ks: Early Studies 360
3. Clinically Investigated Pan-Active Class I PI3K Inhibitors 362
4. Additional Pan-Active Class I PI3K Inhibitors 366
5. Clinically Investigated Isozyme-Selective PI3K Inhibitors 366
6. Pre-Clinical Isozyme-Selective PI3K Inhibitors 368
7. Conclusions 369
References 370
Part V: Infectious Diseases 376
Chapter 18. The Anti-Infective and Anti-Cancer Properties of Artemisinin and its Derivatives 378
1. Introduction 378
2. Antiparasitic Uses of Artemisinin 379
3. Other Therapeutic Uses of Artemisinin 389
4. Toxicity 392
5. Conclusion 394
References 394
Chapter 19. Recent Advances in the Inhibition of Bacterial Type II Topoisomerases 398
1. Introduction 398
2. Inhibition at the ATP-Binding Site 400
3. Inhibition Outside of the ATP-Binding Site 407
4. Conclusion 412
References 412
Chapter 20. Progress towards the Discovery and Development of Specifically Targeted Inhibitors of Hepatitis C Virus 416
1. Introduction 416
2. Specifically Targeted Inhibitors of HCV 417
3. Conclusions 446
References 447
Part VI: Topics in Biology 460
Chapter 21. Inhibitors of Nuclear Hormone Receptor/Coactivator Interactions 462
1. Introduction 462
2. Coregulators of Nuclear Hormone Receptors 464
3. Coactivator Binding Inhibitors 464
4. Summary 474
References 474
Chapter 22. Safety Testing of Drug Metabolites 478
1. Introduction 479
2. Evolution of the MIST Guidance 481
3. Potential Issues Related to Implementation of a Sound MIST Strategy 484
4. Implications of Metabolism in Safety Testing of New Drugs 485
5. Strategy for Implementation of Best Practices 486
6. Role of the Medicinal Chemist 491
7. Summary 491
References 492
Appendix. Decision Tree Flow Diagram 493
Chapter 23. A Path to Innovation: Gene Knockouts Model New Drug Action 494
1. Introduction 494
2. Metabolism 496
3. Gastrointestinal 497
4. Cardiovascular 498
5. Immunology/Hematology 500
6. Rare Genetic Diseases 503
7. Oncology/Ophthalmology 504
8. Central Nervous System 506
9. Can Mouse Knockout Data Guide New Drug Discovery? 507
References 510
PART VII: Topics in Drug Design and Discovery 518
Part VII: Topics in Drug Design and Discovery 518
Chapter 24. Discovery of Novel Positron Emission Tomography Tracers 520
1. Introduction 520
2. PET Imaging 521
3. Discovery of a New PET Tracer for Serotonin 5-HT1B 521
4. Steps Needed to Develop PET Tracers 525
5. PET Tracers as Translational Tools 527
6. New PET Tracers 528
7. Conclusions 530
References 531
Chapter 25. The Use of Isotopically Labeled Compounds in Drug Discovery 534
1. Introduction 534
2. Synthesis of Radiolabeled Compounds 537
3. Human ADME Studies 549
4. Conclusions 551
References 551
Chapter 26. Mechanism-Based Inhibition of CYP3A4 and Other Cytochromes P450 554
1. Introduction 554
2. Reversible, Irreversible, and Quasi-Irreversible Mechanism-Based Inhibition 555
3. Practical Determination 558
4. Inhibition of Cytochromes P450 562
5. Clinical Relevance 568
6. Conclusions 570
Acknowledgments 570
References 570
Chapter 27. Nonclinical Toxicogenomics in the Pharmaceutical Environment 574
1. Introduction 575
2. Evaluation of Liver Toxicogenomics 575
3. Transcriptional Markers of Pharmacology 576
4. Deriving Diagnostic Transcriptional Signatures as Biomarkers 578
5. Percentage Global Transcriptional Change with Drug Treatment 578
6. Correlating Transcriptomics with Histopathology 580
7. Transcriptional Changes Associated with General Toxicity 582
8. Ruling in and out Mechanisms of Toxicity with Toxicogenomics 582
9. Assigning Cause or Effect to Transcriptional Alterations 584
10. Critical Assessment of In Vitro Toxicogenomics Applications 585
11. Transcriptional Responses to Diet 586
12. Toxicogenomics, Genotoxicity, and Carcinogenicity Prediction 588
13. Providing Feedback to Discovery Working Groups 589
14. Conclusion 590
References 591
Part VIII: To Market, To Market:Drugs Introduced in 2008 594
Chapter 28. To Market, To Market - 2008 596
1. Introduction 597
2. Alvimopan (Postoperative Ileus) [4-8] 603
3. Biolimus Drug-Eluting Stent (Anti-Restenotic) [9-13] 605
4. Blonanserin (Antipsychotic) [14-17] 606
5. Ceftobiprole Medocaril (Antibiotic) [18-21] 608
6. Certolizumab Pegol (Crohn’s Disease) [22-25] 611
7. Choline Fenofibrate (Dyslipidemia) [26-29] 613
8. Clevidipine (Antihypertensive) [30-34] 615
9. Dabigatran Etexilate (Anti-Coagulant) [35-38] 617
10. Desvenlafaxine (Antidepressant) [39-43] 619
11. Etravirine (Antiviral) [44-48] 621
12. Fesoterodine (Overactive Bladder) [49-54] 623
13. Fosaprepitant Dimeglumine (Antiemetic) [55-57] 625
14. Icatibant (Hereditary Angiodema) [58-60] 627
15. Lacosamide (Anticonvulsant) [61-63] 629
16. Methylnaltrexone Bromide (Opioid-Induced Constipation) [64-66] 631
17. Pirfenidone (Idiopathic Pulmonary Fibrosis) [67-70] 633
18. Rilonacept (Genetic Autoinflammatory Syndromes) [71-73] 634
19. Rivaroxaban (Anticoagulant, Venous Thromboembolism) [74-75] 636
20. Romiplostim (Antithrombocytopenic) [76-78] 638
21. Sitafloxacin Hydrate (Antibacterial) [79-82] 640
22. Sugammadex (Reversal of Neuromuscular Blockade) [83-87] 642
23. Tafluprost (Antiglaucoma) [88-90] 644
24. Thrombin Alfa (Heostat) [91-92] 646
25. Thrombomodulin (Recombinant) (Anticoagulant) [93-95] 647
References 649
Compound Name, Code Number and Subject Index, Volume 44 652
Cumulative Chapter Titles Keyword Index, Volume 1–44 660
Cumulative NCE Introduction Index, 1983-2008 680
Cumulative NCE Introduction Index, 1983-2008 (By Indication) 702