Reviews: 2016 Medicinal Chemistry Reviews
Volume : | 51 |
Editor-In-Chief : | Manoj C. Desai |
Medicinal Chemistry Reviews is an outstanding 600 page volume providing timely and critical reviews of important topics in medicinal chemistry. It is provided free of charge to MEDI members in electronic format. Members can also order a print copy, for the cost of printing, shipping and handling
Table of contents
Chapter 1 | Lessons From Decades of R&D Management
Lessons From Decades of R&D Management1. The Early Pfizer Years 4 2. Transition to Management 6 3. The 1990s and Pfizer’s Rise to Prominence 7 4. The Beginning of the Mega-Mergers 9 5. And Now for Something Completely Different 12 6. Final Thoughts 14 |
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Chapter 2 | Recent Developments in Neuropeptide S Receptor (NPSR) Research
Recent Developments in Neuropeptide S Receptor (NPSR) Research1. Introduction 17 2. Single-Nucleotide Polymorphism (SNP) 18 2.1 SNP (rs324981) and Anxiety Disorders 18 2.2 SNP (rs324981) and Alcohol Use 20 2.3 SNP (rs324981) and Sleep Regulation 21 2.4 SNP (rs324981) and Influence of Urban Upbringing on Stress 22 2.5 SNP (rs4751440) Originated from Europe Shows Decreased Bioactivity 23 3. Identification of Intracellular Pathways Activated Following NPSR1 Stimulation in Neurons 23 4. Antinociception: Anxiolytic and Pain-Inhibiting Effects of NPS 24 5. Role of NPS in Fear Extinction, Extinction Memory, and Object Recognition Memory 26 6. NPS and Social Aggression in Mice 26 7. NPS as Biomarker in Cancer 28 8. NPS, Cytokines, and Inflammation 28 9. Evolution of the NPS Receptor 28 10. Novel Ligands for NPSR 29 11. Conclusions 31 |
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Chapter 3 | Metabotropic Glutamate Receptors at Thirty: New Insights From Chemical Tools Enabling Mechanistic Understanding
Metabotropic Glutamate Receptors at Thirty: New Insights From Chemical Tools Enabling Mechanistic Understanding1. Introduction 37 2. Group 2 mGluR Activation 39 2.1 mGluR2/3 Agonists 39 2.2 mGluR2 Positive Allosteric Modulators 40 3. Group 2 mGluR Modulation 41 3.1 mGluR5 Positive Allosteric Modulators 42 3.2 mGluR5 Negative Allosteric Modulators 44 3.3 mGluR1 Positive Allosteric Modulators 45 4. Group 3: mGluR4 Receptor Activation 46 4.1 mGluR4 Positive Allosteric Modulators 46 4.2 mGluR4 Agonists 47 4.3 Group 3 mGluR Pan-PAMs 48 5. Conclusions 49 |
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Chapter 4 | Small-Molecule Selective PPAR-gamma Modulators
Small-Molecule Selective PPAR-gamma Modulators1. Introduction 55 2. Recent Discoveries in PPARγ Biology 56 3. Selective PPARγ Modulators 57 3.1 INT131 57 3.2 Balaglitazone 60 3.3 MK-0533 61 3.4 KDT-501 62 3.5 Metaglidasen 63 3.6 FK-614 64 4. Conclusions 64 |
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Chapter 5 | Nonpeptide AT2 Receptor Agonists
Nonpeptide AT2 Receptor Agonists1. Introduction 69 2. Selective Angiotensin II AT2R Agonists 71 2.1 AT2R Stimulation 71 2.2 The Discovery of C21 72 2.3 Structure Activity Relationships 73 2.4 From Selective AT2R Agonists to AT2R Antagonists 75 2.5 In Vivo Pharmacological Effects of AT2R Agonists 76 3. Conclusions 79 |
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Chapter 6 | Recent Developments in Melanin-Concentrating Hormone Receptor 1 Antagonists
Recent Developments in Melanin-Concentrating Hormone Receptor 1 Antagonists1. Introduction 85 1.1 Biology Background 85 1.2 Effect on Sleep 86 1.3 Effect on Anxiety and Depression 86 2. Small-Molecule MCHR1 Antagonists 86 2.1 Clinical Candidates 87 2.2 Recent Reports on MCHR1 Antagonists 91 3. Autoradiography and PET Tracers 94 4. Conclusions and Outlook 94 |
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Chapter 7 | Targeting Necroptosis for Therapeutic Intervention in Inflammatory Diseases
Targeting Necroptosis for Therapeutic Intervention in Inflammatory Diseases1. Introduction 101 2. MLKL Inhibitors 103 3. RIPK3 Inhibitors 106 4. RIPK1 Inhibitors 107 4.1 Type III Inhibitors 107 4.2 Type II Inhibitors 110 5. Conclusions 112 |
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Chapter 8 | Recent Advances in the Discovery and Development of Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists
Recent Advances in the Discovery and Development of Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists1. Introduction 117 2. TRPA1 Antagonists 118 2.1 Xanthine-based Scaffolds 119 2.2 Sulfonamide-based Scaffolds 121 2.3 5,6-Fused Heterocycle-based Scaffolds 123 2.4 Quinazolinone-based Scaffolds 124 2.5 Aryl Amide-based Scaffolds 125 2.6 Miscellaneous Scaffolds 126 3. Clinical Outlook 128 4. Future Outlook 129 4.1 Structure Guided Drug Design 129 4.2 TRPA1/TRPV1 Dual Antagonists 129 4.3 TRPA1 Agonists 130 5. Conclusions 130 |
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Chapter 9 | Small-Molecule Modulators of Protein Arginine Deaminases (PAD)
Small-Molecule Modulators of Protein Arginine Deaminases (PAD)1. Introduction 135 2. Structures of PAD Enzymes 136 3. Inhibitors of PAD Enzymes 137 3.1 Irreversible Inhibitors 137 3.2 Reversible Inhibitors 141 4. Probes 143 5. Conclusion 145 |
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Chapter 10 | Estrogen Receptor Degraders for the Treatment of ER-positive Breast Cancer
Estrogen Receptor Degraders for the Treatment of ER-positive Breast Cancer2. Selective Estrogen Receptor Degraders (SERDS) Approved or in Clinical Trials 152 2.1 Fulvestrant 152 2.2 GW5638/7604 153 2.3 GDC-0810 154 2.4 AZD9496 155 2.5 RAD1901 155 2.6 Bazedoxifene 156 3. SERDs in Preclinical Testing 157 3.1 Tetrahydroisoquinolinols (THIQs) 157 3.2 Coumarins 157 3.3 Chromenes 158 3.4 Benzothiophenes 158 3.5 Benzoannulens 159 3.6 Proteolysis targeting chimeras (PROTACs) 159 4. Challenges and Future Directions 160 5. Conclusions 161 |
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Chapter 11 | Small-Molecule Modulators of Keap1-Nrf2
Small-Molecule Modulators of Keap1-Nrf21. Introduction 167 1.1 Oxidative Stress and Antioxidant Response 167 1.2 Nrf2 Function in the Antioxidant Response 168 1.3 Therapeutic Function of Nrf2 in Disease States 170 1.3.1 Role in Oncology 170 1.3.2 Role in CNS and Respiratory Diseases 170 1.4 Structure Function of Keap1-Nrf2 171 2. Small-Molecule Activators of the Keap1-Nrf2 Mediated Antioxidant Response 172 2.1 Covalent Cysteine Modifiers 172 2.1.1 Sulforaphanes 172 2.1.2 Fumarates 172 2.1.3 Chalcones and Vinyl Sulfones 173 2.1.4 Oleanane Triterpenoid Derivatives 173 2.1.5 Quinones and Catechols 174 2.2 Keap1-Nrf2 PPI Disruptors 175 2.2.1 Naphthalene Sulfonamides 175 2.2.2 Carboxylic Acids 176 2.2.3 Triazoles 177 2.3 Undefined Mechanism of Action 177 3. Small-Molecule Inhibitors of the Keap1-Nrf2 Mediated Antioxidant Response 177 3.1 Keap1-Nrf2 Pathway Inhibitors 178 4. Conclusions 178 |
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Chapter 12 | Small-Molecule Modulators Targeting the Unfolded Protein Response Sensor IRE1-alpha
Small-Molecule Modulators Targeting the Unfolded Protein Response Sensor IRE1-alpha1. Introduction 186 2. Kinase Domain Inhibitors of IRE1α 189 2.1 RNase Activators 190 2.2 RNase Inhibitors 194 3. RNase Domain Inhibitors of IRE1α 195 4. Challenges and Future Directions 198 |
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Chapter 13 | Approaches to Eradicate HIV Infection
Approaches to Eradicate HIV Infection1. Barriers to HIV Eradication 208 1.1 Latent HIV Reservoir 209 1.2 The Persistent Reservoir 210 1.3 Quantification of the Latent Reservoir 210 2. Latency Disruption 210 2.1 Histone Deacetylase Inhibitors 211 2.2 Epigenetic Regulators Beyond HDAC Inhibitors 213 2.3 Protein Kinase C Agonists 214 2.4 BIRC2 Inhibitors 215 2.5 Toll-Like Receptor Activators 215 2.6 Screening Approaches to Identify Novel Agents/Mechanisms 216 3. Elimination of Infected Cells 217 3.1 Antibody and Antibody-Derived Molecules 217 3.2 Harnessing Cytotoxic T-Lymphocyte Response 218 3.3 Therapeutic Vaccine Strategy 219 3.4 Gene Therapy 219 4. Conclusions and Outlook 220 |
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Chapter 14 | Therapeutics for Treatment of Ebola and Other Filovirus Infections
Therapeutics for Treatment of Ebola and Other Filovirus Infections1. Introduction 227 1.1 Pathogenesis 228 1.2 Virus Replication 230 1.3 Antiviral Assays 230 1.4 Model Systems for Drug Discovery 231 2. Antibody-Based Therapeutics (ZMapp™) 231 3. Oligomeric Nucleic Acid-Based Therapeutics 232 3.1 TKM-Ebola 232 3.2 AVI-7537/AVI-7288 233 4. Small-Molecule Therapeutics 234 4.1 Favipiravir (T-705) 235 4.2 Brincidofovir (CMX-001) 235 4.3 Galidesivir (BCX-4430) 236 4.4 GS-5734 236 5. Conclusion 237 |
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Chapter 15 | Polymyxins Targeting the Outer Membrane of Gram-Negative Bacteria
Polymyxins Targeting the Outer Membrane of Gram-Negative Bacteria1. Introduction 243 1.1 Polymyxins and Medical Need 243 1.2 Polymyxins and the Outer Membrane of Gram-Negative Bacteria 246 1.3 Acquired Resistance to Polymyxins 246 2. Novel Direct-Acting Antimicrobial Polymyxins 247 2.1 Variation in the Cyclic Peptide 247 2.2 Changes in the Linear Peptide and the N-Terminal Moiety 248 3. Polymyxins as Potentiators 251 4. Assessing the Nephrotoxic Potential of Polymyxins 253 5. Concluding Remarks 255 |
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Chapter 16 | Recent Developments in Agents for the Treatment of Age-Related Macular Degeneration and Stargardt Disease
Recent Developments in Agents for the Treatment of Age-Related Macular Degeneration and Stargardt Disease1. Introduction 261 2. Inhibition of Retinal Choroidal Neovascularization 263 2.1 Anti-VEGF Monoclonal Antibodies and VEGF-Trap/Fusion Proteins 263 2.2 Anti-VEGF and PDGF-B Aptamers 264 2.3 Receptor Tyrosine Kinase Inhibitors 264 2.4 mTOR Inhibitors 266 2.5 Other Anti-Angiogenesis Approaches 266 3. Visual Cycle Inhibitors and Modulators 267 3.1 RPE65 Isomerase 268 3.2 RBP4 Antagonists 269 3.3 C20-D3 Vitamin A and Retinaldehyde Traps 270 4. Complement Pathway Inhibitors 271 4.1 Complement Factor D 272 4.2 C3 and C5 Inhibitors 272 5. Neuroprotective Agents 273 6. Clinical Synopsis 273 7. Conclusion 274 |
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Chapter 17 | Targeting beta-Amyloid and Tau Protein Oligomers and Aggregates as a Novel Approach to the Treatment of Alzheimer's Disease
Targeting beta-Amyloid and Tau Protein Oligomers and Aggregates as a Novel Approach to the Treatment of Alzheimer's Disease1. Introduction 282 2. Biochemical, Cellular And Animal Models For Aβ And Tau Aggregation 282 2.1 Aβ Biochemical 282 2.2 Aβ Cellular 283 2.3 Tau Biochemical 284 2.4 Tau Cellular 284 2.5 Aβ and Tau Aggregation Animal Models 285 3. Protein Misfolding/Oligomerization Inhibitors 286 3.1 Direct Inhibition of Tau Aggregation 286 3.2 Inhibitors of Post-Translational Modification Of Tau Protein 286 3.2.1 Inhibitors of Tau Hyperphosphorylation: GSK-3β Inhibitors 286 3.2.2 Inhibitors of Tau Hyperphosphorylation: CDK5 Kinase Inhibitors 287 3.2.3 cAMP–protein Kinase A (PKA) 287 3.2.4 Tau O-GlcNAcylation Enhancers 288 3.3 Inhibitors Affecting Tau Clearance 289 3.4 Immunotherapy Against Tau 289 3.5 Inhibitors of Aβ Aggregation 290 3.6 Aβ Clearing Agents 291 |
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Chapter 18 | Development of VEGFR Inhibitors as Antiangiogenic Agents
Development of VEGFR Inhibitors as Antiangiogenic Agents1. Introduction 299 2. Vascular Endothelial Growth Factor (VEGF) in Angiogenesis 300 3. Structural Aspects of the VEGFR Kinase Domain: Development and Structure Activity Relationships 301 4. Tyrosine Inhibitors of VEGFR 303 4.1 Table of Approved Drugs 303 4.2 Molecules in Clinical Trials 304 5. Conclusion 307 |
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Chapter 19 | Recent Developments in Chiral Phosphorothioate Oligonucleotides
Recent Developments in Chiral Phosphorothioate Oligonucleotides1. Introduction 313 2. Recent Developments 315 2.1 siRNA 315 2.2 Antisense 317 2.3 Nucleic Acid Adjuvants 321 3. Synthesis of Chiral Phosphorothioates 322 4. Conclusions 323 |
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Chapter 20 | Boron in Medicinal Chemistry
Boron in Medicinal Chemistry1. Introduction 329 2. Boron-Based Bioisosterism and Advantages in Enzyme Inhibition 330 3. Therapeutic Areas With Active Boron Research 333 3.1 Antiparasitic Agents 333 3.2 Antibacterial Agents 335 3.2.1 β-Lactamase inhibitors 335 3.2.2 Aminoacyl-tRNA inhibitors 336 3.3 Anti-inflammatory Agents 336 3.3.1 Phosphodiesterase (PDE) 4 Inhibitors 336 3.3.2 Other Anti-Inflammatory Agents 337 4. Mutagenicity of Boron-containing Compounds 338 5. Boron-containing Drugs on the Market or Late Development 339 6. Conclusions 340 |
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Chapter 21 | Protein Degraders: Moving Towards Therapeutically Viable Agents
Protein Degraders: Moving Towards Therapeutically Viable Agents1. Introduction 347 2. Description of Protein Degraders 348 2.1 Description of Protein Degraders and E3 Ligases 348 2.2 Advantages/Challenges of Protein Degraders Compared to Classical Targeting Ligands 350 2.3 Characterization of Protein Degraders 351 3. Classes of Protein Degraders Based on E3 Ligase 352 3.1 β-TRCP-Binding PROTACs 352 3.2 IAP-Binding Protein Degraders 353 3.3 MDM2-Binding Protein Degraders 355 3.4 Cereblon-Binding Protein Degraders 356 3.5 VHL-Based Protein Degraders 360 4. Conclusion 368 |
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Chapter 22 | Case History: The Discovery of the First Hepatitis C Virus NS5A Replication Complex Inhibitor Daclatasvir (Daklinza™)
Case History: The Discovery of the First Hepatitis C Virus NS5A Replication Complex Inhibitor Daclatasvir (Daklinza™)1. Introduction 375 2. Screening for the Lead 376 3. Early Lead Optimization and the Discovery of Dimeric Species 377 4. Optimization of Dimeric Leads to Pan-Genotype HCV Inhibitors and Daclatasvir 381 5. The Clinical Program 389 6. Conclusion 393 |
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Chapter 23 | Case History: Vorapaxar (Zontivity®): A First-In-Clas Protease-Activated Receptor-1 (PAR-1) Antagonist Antiplatelet Agent
Case History: Vorapaxar (Zontivity®): A First-In-Clas Protease-Activated Receptor-1 (PAR-1) Antagonist Antiplatelet Agent1. Introduction 399 2. Protease-Activated Receptor-1 (PAR-1) as an Antiplatelet Target 401 3. Medicinal Chemistry Efforts Leading to the Identification of Vorapaxar 402 3.1 Lead Identification via HTS 402 3.2 SAR of Himbacine-Based PAR-1 Antagonists 403 3.3 Discovery of First-Generation PAR-1 Antagonist SCH 205831 406 3.4 Metabolism-Based Identification of a Backup Candidate 407 3.5 Aryl Himbacine PAR-1 Antagonists 408 3.6 Introduction of Heterocyclic C-ring 410 3.7 Discovery of Vorapaxar (SCH 530348) 411 4. Pharmacological Characterization of Vorapaxar 412 5. Clinical studies of Vorapaxar 414 6. Conclusion 416 |
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Chapter 24 | New Chemical Entities Entering Phase III Trials in 2015
New Chemical Entities Entering Phase III Trials in 2015 |
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Chapter 25 | To Market, To Market--2015
To Market, To Market--20151. Alirocumab (antihypercholesterolemic) 454 2. Aripiprazole lauroxil (antipsychotic) 456 3. Avibactam in combination with ceftazidime (antibacterial) 458 4. Brexpiprazole (antidepressant; antipsychotic) 460 5. Cangrelor (antiplatelet) 462 6. Cariprazine (antipsychotic) 465 7. Chidamide (anticancer) 467 8. Cobimetinib (anticancer) 469 9. Daratumumab (anticancer) 471 10. Dinutuximab (anticancer) 473 11. Elotuzumab (anticancer) 475 12. Eluxadoline (irritable bowel syndrome) 477 13. Evolocumab (antihypercholesterolemic) 479 14. Flibanserin (female sexual dysfunction) 482 15. Idarucizumab (anticoagulant antidote) 483 16. Isavuconazonium sulfate (antifungal) 485 17. Ixazomib (anticancer) 487 18. Lenvatinib mesylate (anticancer) 489 19. Lesinurad (gout) 491 20. Lumacaftor in combination with ivacaftor (cystic fibrosis) 493 21. Lusutrombopag (thrombocytopenia) 494 22. Mepolizumab (antiasthma) 496 23. Necitumumab (anticancer) 498 24. Omarigliptin (antidiabetic) 500 25. Osimertinib (anticancer) 502 26. Ozenoxacin (antibacterial) 503 27. Palbociclib (anticancer) 505 28. Panobinostat (anticancer) 507 29. Polmacoxib (antiarthritis) 509 30. Rolapitant (antiemetic) 510 31. Sacubitril in combination with valsartan (heart failure) 512 32. Safinamide (Parkinson’s Disease) 515 33. Selexipag (pulmonary hypertension) 517 34. Sonidegib (anticancer) 519 35. Tenofovir Alafenamide in combination with cobicistat, elvitegravir, emtricitabine (antiviral) 520 36. Tipiracil in combination with trifluridine (anticancer) 522 37. Uridine Triacetate (antidote to fluorouracil; hereditary orotic aciduria) 525 38. Zabofloxacin (antibacterial) 526 |