Elsevier S & T

Annual Reports in Medicinal Chemistry

Macor, John E.

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Table of contents
  • Contentsv
  • Contributorsxv
  • Prefacexvii
  • Part I: Central Nervous System Diseases – ROBICHAUD1
  • Chapter 1. Potential CNS Applications for Phosphodiesterase Enzyme Inhibitors3
  • 1. Introduction3
  • 2. PDE2 Inhibitors4
  • 3. PDE4 Inhibitors6
  • 4. PDE9 Inhibitors7
  • 5. PDE10 Inhibitors8
  • 6. PDE11 Inhibitors10
  • 7. Summary10
  • References11
  • Chapter 2. Recent Developments in Monoamine Reuptake Inhibitors13
  • 1. Introduction13
  • 2. Single Action Reuptake Inhibitors14
  • 3. Dual Reuptake Inhibitors18
  • 4. Triple Reuptake Inhibitors (TRIs)21
  • 5. Conclusion23
  • References23
  • Chapter 3. Secretase Inhibitors and Modulators for the Treatment of Alzheimer’s Disease27
  • 1. Introduction27
  • 2. Inhibitors of BACE28
  • 3. Inhibitors of γ-Secretase34
  • 4. Modulators of γ-Secretase39
  • 5. Summary42
  • References42
  • Chapter 4. Recent Advances in Drug Discovery of Histamine H3 Antagonists49
  • 1. Introduction49
  • 2. Clinical Applications of H3 Receptor Antagonists51
  • 3. Pharmacophores and Modeling53
  • 4. Design Strategies and Structure–Activity Advances53
  • 5. H3 Antagonists with a Dual Mechanism58
  • 6. Future Perspectives59
  • References59
  • Chapter 5. Recent Advances in the Treatment of Insomnia63
  • 1. Introduction63
  • 2. GABAA Receptor Modulators65
  • 3. Melatonin Receptor Agonists68
  • 4. Orexin Receptor Antagonists71
  • 5. Histaminergic and Serotoninergic Modulators75
  • 6. Concluding Remarks77
  • References78
  • Chapter 6. Advances in Transient Receptor Potential Modulators81
  • 1. Introduction81
  • 2. Small Molecule TRP Modulators82
  • 3. Conclusion89
  • References89
  • Part II: Cardiovascular and Metabolic Diseases – STAMFORD93
  • Chapter 7. Case History: JANUVIA’ (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for95
  • 1. Introduction95
  • 2. Pathogenesis of Type 2 Diabetes96
  • 3. Rationale for the Use of DPP-4 Inhibitors to Treat Type 2 Diabetes97
  • 4. MRL’s DPP-4 Inhibitor Program: Threo- and Allo-Isoleucyl Thiazolidides98
  • 5. Medicinal Chemistry Efforts Leading to Sitagliptin100
  • 6. Properties of Analog 27 and Sitagliptin105
  • 7. Clinical Studies of Sitagliptin106
  • 8. Conclusion107
  • References107
  • Chapter 8. Cathepsin K Inhibitors111
  • 1. Introduction111
  • 2. New Biology112
  • 3. Recent Advances in Inhibitor Design116
  • 4. Clinical Data123
  • 5. Conclusions124
  • Acknowledgement124
  • References124
  • Chapter 9. New Nonpeptide-Binding GPCRs as Targets for Diabetes and the Metabolic Syndrome129
  • 1. Introduction129
  • 2. GPR119130
  • 3. GPR40 Family134
  • 4. GPR120138
  • 5. GPR55 and GPR35138
  • 6. GPR109A and GPR109B139
  • 7. Conclusions141
  • References141
  • Chapter 10. Novel Selective Estrogen Receptor Modulators (SERMs)147
  • 1. Introduction147
  • 2. SERMs for Hot Flushes148
  • 3. Ovarian Selective SERMs149
  • 4. ERα Selective Serms151
  • 5. Other Novel Serm Scaffolds153
  • 6. Steroid-Derived Scaffolds155
  • 7. Nonclassical Estrogen Signaling156
  • 8. Conclusion157
  • References158
  • Chapter 11. Lipid-Metabolizing Enzymes as Targets for Dyslipidemia and Insulin Resistance161
  • 1. Introduction161
  • 2. Lipid Absorption and Mobilization162
  • 3. Triglyceride Synthesis165
  • 4. Fatty Acid Synthesis and Metabolism167
  • 5. Conclusion171
  • References172
  • Chapter 12. Recent Trends in HDL Modulating Therapies177
  • 1. Introduction177
  • 2. HDL and Atherosclerosis178
  • 3. Scope and Limitations of Marketed Therapies178
  • 4. Emerging Clinical Compounds183
  • 5. Pre-Clinical Developments186
  • 6. Conclusion187
  • References188
  • Part III: Inflammation/Pulmonary/GI – BARRISH193
  • Chapter 13. Case History on Tegaserod (Zelnormreg®/Zelmacreg®)195
  • 1. Introduction195
  • 2. Discovery of the 5-HT4 Receptor in the GI Tract196
  • 3. Test Systems Addressing 5-HT4 Receptor Agonist Activity197
  • 4. From Serotonin to Tegaserod199
  • 5. Profiling Studies203
  • 6. Clinical Phase II/III Studies206
  • 7. Conclusion207
  • References208
  • Chapter 14. Advances in the Discovery of CC Chemokine Receptor 2 Antagonists211
  • 1. Introduction211
  • 2. Recent Biology212
  • 3. Recent Medicinal Chemistry215
  • 4. Conclusion223
  • References223
  • Chapter 15. Semicarbazide Sensitive Amine Oxidase and Vascular Adhesion Protein-1: One Protein Being229
  • 1. Introduction230
  • 2. Molecular Biology of the Copper-Containing Amine Oxidase Family232
  • 3. Co-factor and Mechanism of the Amine Oxidase Activity233
  • 4. Structural Biology233
  • 5. Therapeutic Opportunities234
  • 6. Drug Discovery235
  • 7. SSAO/VAP-1 Inhibitors235
  • 8. Conclusion240
  • 9. Abbreviations240
  • References241
  • Chapter 16. Sphingosine 1-Phosphate Type 1 Receptor Modulators: Recent Advances and Therapeutic Pote245
  • 1. Introduction245
  • 2. S1P1 Agonists249
  • 3. S1P1 Antagonists258
  • 4. Conclusions259
  • References260
  • Chapter 17. MAP Kinase Inhibitors in Inflammation and Autoimmune Disorders265
  • 1. Introduction265
  • 2. Inhibitors of ERK Pathway268
  • 3. Inhibitors of JNK Pathway270
  • 4. Inhibitors of p38 Pathway274
  • 5. Conclusion275
  • References275
  • Part IV: Cancer and Infectious Diseases – MYLES279
  • Chapter 18. Recent Progress on Novel HCV Inhibitors281
  • 1. Introduction281
  • 2. Novel Compounds in the Discovery/Preclinical Stage282
  • 3. Conclusion294
  • References294
  • Chapter 19. Small Molecule CCR5 and CXCR4-Based Viral Entry Inhibitors for Anti-HIV Therapy Currentl301
  • 1. Introduction301
  • 2. CCR5 Inhibitors302
  • 3. CXCR4 Inhibitors309
  • 4. Conclusions315
  • Note316
  • References316
  • Chapter 20. Small-Molecule Inhibitors of Glutathione S-Transferase P1-1 as Anticancer Therapeutic Ag321
  • 1. Introduction321
  • 2. Types of Inhibitors322
  • 3. Conclusions332
  • References332
  • Chapter 21. Recent Advances in the Medicinal Chemistry of Histone Deacetylase Inhibitors337
  • 1. Introduction337
  • 2. Zinc-Dependent HDAC Inhibitors338
  • 3. NAD-Dependent HDAC Modulators344
  • 4. Conclusion346
  • References346
  • Chapter 22. New Developments in Antibacterial Drug R&D349
  • 1. Introduction349
  • 2. Updates of Established Classes of Antibiotics353
  • 3. Future Antibacterial Pipeline: Inhibitors of New Targets358
  • 4. Future Outlook360
  • References361
  • Chapter 23. Small Molecule Inhibitors of AKT/PKB Kinase as a Strategy for Treating Cancer365
  • 1. Introduction365
  • 2. PI3K/AKT Kinase Pathway Inhibitors in Pre-Clinical Development366
  • 3. PI3K/AKT Kinase Pathway Inhibitors in Clinical Trials371
  • 4. Conclusions373
  • References373
  • Part V: Topics in Biology – LOWE377
  • Chapter 24. Spleen Tyrosine Kinase (Syk) Biology, Inhibitors and Therapeutic Applications379
  • 1. Introduction379
  • 2. Syk Kinase380
  • 3. Structural Biology of Syk Kinase380
  • 4. Syk Kinase as a Therapeutic Target for Disease382
  • 5. Status of Small Molecule Inhibitors of Syk Kinase386
  • 6. Conclusion389
  • References389
  • Chapter 25. Systems Biology and Kinase Signaling393
  • 1. Complexity and Scope in Systems Kinase Biology393
  • 2. Positive and Negative Feedback Loops394
  • 3. An Example of the Practical Application of Systems Biology: ErbB Signaling396
  • 4. Conclusion399
  • 5. Acronyms Used399
  • References400
  • Chapter 26. The Molecular Libraries Screening Center Network (MLSCN): Identifying Chemical Probes of401
  • 1. Introduction402
  • 2. Role of Chemistry in the MLSCN408
  • 3. Novel Probes from the MLSCN409
  • 4. Future Outlook and Conclusions414
  • References415
  • Chapter 27. The Application of Transcriptional Profiling in Model Connectivity and Lead Assessment i417
  • 1. Introduction417
  • 2. Transcriptional Profiling Technology: State of the Art, and Foreseeable Future418
  • 3. Interconnecting Disease, Target Validation Models, and Pharmacological Response419
  • 4. Comparing Selectivity of Pharmacological Response in Lead Assessment422
  • 5. Conclusions425
  • References426
  • Part VI: Topics in Drug Design and Discovery – DESAI429
  • Chapter 28. Fragment-Based Lead Discovery431
  • 1. Introduction431
  • 2. Examples of Fragment Hit Identification432
  • 3. Examples of Fragments Progressed into Nanomolar Leads435
  • 4. Commentary and Discussion of Key Concepts443
  • 5. Outlook445
  • References446
  • Chapter 29. Computational Models for ADME449
  • 1. Introduction449
  • 2. Basic Computed Descriptors for Drug-Likeness451
  • 3. Solubility452
  • 4. Intestinal Absorption455
  • 5. Blood-Brain-Barrier Penetration457
  • 6. Metabolism463
  • 7. Conclusion464
  • References465
  • Chapter 30. Prediction of Human Volume of Distribution Using in vivo, in vitro, and in silico Approa469
  • 1. Introduction469
  • 2. Definitions of Volume of Distribution470
  • 3. Predicting Human Volume of Distribution from Chemical, in vitro, and in vivo Data474
  • 4. Conclusions485
  • References488
  • Chapter 31. Plasma Protein Binding and the Free Drug Principle: Recent Developments and Applications489
  • 1. Introduction489
  • 2. Refinements in Understanding of the Free Drug Principle490
  • 3. Applications from the Medicinal Chemistry Literature494
  • 4. Computational Studies497
  • 5. Exceptions to the Free Drug Principle498
  • 6. Advances in Methodology for Measuring Plasma Protein Binding498
  • References499
  • Part VII: To Market, To Market – 2006503
  • Chapter 32. To Market, To Market – 2006505
  • References550
  • Compound Name, Code Number and Subject Index. Vol. 42555
  • Cumulative Chapter Titles Keyword Index, Vol. 1–42565
  • Cumulative NCE Introduction Index, 1983–2006583
  • Cumulative NCE Introduction Index, 1983–2006 (By Indication)603
  • Color Plate SectionColor Plate 1
Book details
  • Vendor Elsevier S & T
  • SKU 9780123739124
  • ISBN-13 9780080554877
  • Author Macor, John E.
  • Category Medical
  • Subject Pharmacology

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Annual Reports in Medicinal Chemistry provides timely and critical reviews of important topics in medicinal chemistry together with an emphasis on emerging topics in the biological sciences, which are expected to provide the basis for entirely new future therapies.

* Critical reviews of the previous year’s literature in many topics of interest to medicinal chemists
* Highlights major developments in medicinal chemistry
* Includes a comprehensive set of cumulative indexes to easily locate topics in all published volumes