Reviews: 2017 Medicinal Chemistry Reviews
Volume : | 52 |
Editor-In-Chief : | Joanne J. Bronson |
Medicinal Chemistry Reviewsis 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 | Discovery of TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways
Discovery of TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways1. Introduction 3 2. Strategy for Drug Screening 5 3. Hit Identification and Strategy for Chemistry 6 4. Candidate Identification 7 5. Characterization of Compounds 6e and 7b 15 5.1 PDE10A Selectivity and PK Profile of 6e and 7b 15 5.2 In Vivo Pharmacological Profile of 6e and 7b 15 5.3 Safety Profile of 7b 18 6. Conclusions 19 Haruhide Kimura and Takahiko Taniguchi |
|
Chapter 2 | PDE1 Inhibition: Potential for the Treatment of Cognitive Impairment
PDE1 Inhibition: Potential for the Treatment of Cognitive Impairment1. Introduction 25 2. Vinpocetine and Early Non-Selective PDE1 Inhibitors 28 3. Recent Medicinal Chemistry and Pharmacology of Selective PDE1 Inhibitors 29 4. PDE1 Structural Biology 33 5. Patent Landscape 35 5.1 Fused 6,5-Bicyclic Rings 35 5.2 Fused 6,6-Bicyclic Rings 37 5.3 Fused Tricyclic Rings 37 6. Conclusions 38 Brian Dyck, Marco Peters, and J. Guy Breitenbucher |
|
Chapter 3 | Discovery of the ALK/ROS1 Inhibitor, Lorlatinib (PF-06463922)
Discovery of the ALK/ROS1 Inhibitor, Lorlatinib (PF-06463922)1. Introduction 45 2. Next-Generation ALK Program—Acyclic (or Non-Macrocyclic) Chemical Space 48 3. Macrocyclic Inhibitors—Discovery of Lorlatinib (16) 51 4. Selectivity Strategy 54 5. CNS Exposure 57 6. Acyclics versus Macrocycles 60 7. Overview of Lorlatinib (16) 61 Paul F. Richardson and Ted W. Johnson |
|
Chapter 4 | Advances and Insights from CNS G Protein-Coupled Receptor Crystallography
Advances and Insights from CNS G Protein-Coupled Receptor Crystallography1. Introduction 69 2. Overview of GPCR Structural Biology Approaches 72 3. Overview of Orthosteric Structures of CNS GPCRs 74 4. Allosteric Modulation of CNS GPCR Targets 80 5. Conclusions John A. Christopher, Miles Congreve, Francesca Deflorian, and Fiona H. Marshall |
|
Chapter 5 | Recent Advances in BACE1 Biology and Inhibitors in Clinical Development
Recent Advances in BACE1 Biology and Inhibitors in Clinical Development1. Introduction 89 2. BACE1 and the Amyloid Hypothesis 90 3. Safety and Tolerability of BACE Inhibition 91 3.1 Bace1 Knockout Mice 91 3.2 Bace2 Knockout Mice 92 3.3 Cathepsin D 93 4. Compounds in Advanced Clinical Development 94 4.1 Verubecestat 94 4.2 Lanabecestat, Elenbecestat, JNJ54861911, CNP520 97 5. Conclusions 101 Jared N. Cumming, Matthew E. Kennedy, and Andrew W. Stamford |
|
Chapter 6 | Cardiac Sarcomere Activation and its Therapeutic Application in Heart Failure
Cardiac Sarcomere Activation and its Therapeutic Application in Heart Failure1. Introduction 109 1.1 Introduction to Heart Failure (HF) 109 1.2 Basic Cardiac Sarcomere Muscle Biology 111 2. Increasing Cardiac Contractility: An Approach to HFrEF 112 2.1 Early Approaches to Cardiac Sarcomere Activation 112 2.2 Current Approaches to Cardiac Sarcomere Activation 114 3. Selective Cardiac Myosin Activators 115 3.1 Omecamtiv Mecarbil 115 3.1.1 Omecamtiv Mecarbil: Optimization 115 3.1.2 Omecamtiv Mecarbil: Mechanism of Activation Studies 117 3.1.3 Omecamtiv Mecarbil: In Vivo Proof of Concept 118 3.2 MYK-491 118 4. Clinical Progress of Cardiac Sarcomere Activators 118 4.1 Levosimendan 119 4.2 Pimobendan 119 4.3 Omecamtiv Mecarbil 119 5. Conclusions 120 Antonio Romero and Bradley P. Morgan |
|
Chapter 7 | Development of Sodium-Dependent Phosphate Co-Transporter 2b Inhibitors for Treatment of Hyperphosphatemia
Development of Sodium-Dependent Phosphate Co-Transporter 2b Inhibitors for Treatment of Hyperphosphatemia1. Introduction 125 2. Early Discovery of Intestinal Sodium-Dependent Phosphate Transporter Inhibitors 127 3. Investigation of Sodium-Dependent Phosphate Co-Transporter 2b Inhibitors 130 3.1 Triazoles 131 3.2 Acylhydrazones 132 3.3 Thiophene Amides 133 3.4 Anthranilic Amides and Related Analogs 136 3.5 Dihydropyridazine-3,5-diones 141 4. Clinical Studies and Future Perspectives 142 Yanping Xu and Dariusz Wodka |
|
Chapter 8 | Glucokinase Activators for the Treatment of Diabetes
Glucokinase Activators for the Treatment of Diabetes1. Introduction 147 1.1 Introduction to Diabetes 147 1.2 Glucokinase 147 2. Glucokinase Activators 149 2.1 Background 149 2.2 Selected GKA Publications Prior to 2014 150 2.3 Selected GKA Publications After 2014 153 2.3.1 Liver-Selective GKAs 153 2.3.2 Novel “Carbon-Centered” GKAs 154 2.3.3 Novel “Aromatic-Centered” GKAs 154 3. Conclusions 157 Paul Dransfield |
|
Chapter 9 | Recent Advances in the Discovery of CSFqR Inhibitors for Autoimmune Diseases
Recent Advances in the Discovery of CSFqR Inhibitors for Autoimmune Diseases1. Introduction 165 1.1 CSF1R as an Immunological Target 165 1.2 Role in Disease Pathology 166 1.3 Potential Concerns Associated with Inhibition 167 2. Recent Small-Molecule CSF1R Inhibitors 168 2.1 Heteroarylamides 168 2.2 Amidoquinolines and Amidocinnolines 170 2.3 Other Chemotypes 171 3. Clinical Data 173 4. Conclusions 174 Dawn M. George, Michael Hoemann, and Jacqueline Loud |
|
Chapter 10 | Diverse Drugs with Gastrointestinal-Restricted Delivery
Diverse Drugs with Gastrointestinal-Restricted Delivery1. Introduction 179 2. Ileal Bile Acid Transporter (IBAT) Inhibitors 180 3. TGR5 Agonists 182 4. Pan JAK Inhibitors 183 5. “Narrow Spectrum” Tyrosine Kinase Inhibitors 184 6. RET Kinase Inhibitors 185 7. α4-β7 Integrin Antagonist (PTG-100) 185 8. NHE3 Inhibitors 187 9. F1F0-ATPase Modulator 188 10. Summary/Lessons Observed 189 Thomas D. Aicher, Clarke B. Taylor, and Peter L. Toogood |
|
Chapter 11 | ROR-gamma-T Modulators for Th17-Driven Diseases: Progress Into the Clinic
ROR-gamma-T Modulators for Th17-Driven Diseases: Progress Into the Clinic1. Introduction 195 1.1 The ROR Family 196 1.2 Structure of RORγ and Endogenous Ligands 196 1.3 Expression and Function of RORγ and RORγt 198 1.3.1 RORγt Master Regulator of TH17 and Other Immune Cells 198 1.3.2 RORγ Functions in Non-Immune Cells 199 2. Role of RORγt in Disease 199 2.1 Autoimmune Diseases 199 2.2 Other Indications 201 3. Small-Molecule Modulators of RORγt 202 3.1 Ligands of the Canonical Binding Pocket 202 3.1.1 Hexafluoroisopropanols 202 3.1.2 Tertiary Sulfonamides 202 3.1.3 Sulfonamides of Cyclic Amines 204 3.1.4 Biaryls 205 3.1.5 Alkylsulfonylbenzyl Compoundslls 206 3.1.6 Piperazines 207 3.1.7 Miscellaneous Compounds 208 3.2 Allosteric Ligands 209 4. Clinical Development of RORγt Modulators 211 5. Conclusions 212 Colin M. Tice, Yuri Bukhtiyarov, Ya-Jun Zheng, Deepak Lala, and Suresh B. Singh |
|
Chapter 12 | Small Molecules for Cancer Immunotherapy
Small Molecules for Cancer Immunotherapy1. Introduction 221 2. IDO and TDO Enzymes 222 3. Toll-Like Receptors 223 4. Adenosine Pathway 224 5. Arginine Metabolism 226 6. PGE2 227 7. Chemokines and Chemokine Receptors 227 7.1 CXCR1/CXCR2 228 7.2 CXCR4 229 7.3 CCR5 230 7.4 CCR2 230 7.5 CCR4 231 8. Kinases 232 9. Conclusion 234 Timothy P. Heffon and Bryan K. Chen |
|
Chapter 13 | Beyond PARP: Inhibitors of DNA Repair Processes as Potential Therapeutic Agents for Cancer
Beyond PARP: Inhibitors of DNA Repair Processes as Potential Therapeutic Agents for Cancer1. Introduction 244 1.1 The DNA Damage Response (DDR) in Cancer—Complexity and Redundancy 244 1.2 Exploiting the DDR to Date—the PARP Inhibitors 245 1.3 Challenges for Drug Discovery 245 1.3.1 Druggability of Emerging Target Classes 245 1.3.2 Biological and Screening Challenges 246 2. DDR-Related Kinases 247 2.1 ATM and ATR Kinases—Similarities and Differences 247 2.2 ATM Inhibitors 248 2.3 ATR Inhibitors 249 2.4 Clinical Progression 251 3. Exploiting Compromised DDR via Wee1 Kinase 252 3.1 Wee1 Inhibitors 252 3.2 Single Agent vs. Combination Studies Reveal Novel Therapeutic Options 253 3.3 Clinical Progression 254 4. PARG Inhibitors 254 4.1 The Role of PARG 254 4.2 PARG Inhibitors 255 4.3 Clinical Implications 256 5. Future Directions and Conclusions 257 Allan Michael Jordan and Kate Mary Smith |
|
Chapter 14 | Small-Molecule Antagonists of Mcl-1
Small-Molecule Antagonists of Mcl-11. Introduction 263 2. Small-Molecule Selective Mcl-1 Antagonists 266 2.1 AMG 176 266 2.2 S63845 267 2.3 AZD5991 269 2.4 Indole-2-carboxylate Inhibitors 270 2.5 Indole-2-(methylsulfonyl)carboxamide Inhibitors 272 2.6 Arylboronic Acid Covalent Inhibitors 273 2.7 Cyclopeptidic Inhibitors 274 3. Conclusions 275 Joshua P. Taygerly and Daniel W. Robbins |
|
Chapter 15 | Novel Bacterial Type II Topoisomerase Inhibitors
Novel Bacterial Type II Topoisomerase Inhibitors1. Introduction 281 2. Critical Medicinal Chemistry Objectives 284 3. Approaches to Targeting Gram-Positive Pathogens 286 3.1 Oxabicyclooctane Linkers 286 3.2 Tetrahydropyran Linkers 287 3.3 Carboxypiperidine Linkers 288 3.4 Aminopiperidine Linkers 289 4. Approaches to Targeting Gram-Negative Pathogens 290 4.1 Aminocyclohexane Linkers 290 4.2 Tetrahydropyran Linkers 292 4.3 Fused Tricyclic DNA-binding Moieties 293 5. Pharmacokinetic/Pharmacodynamic Relationships 293 6. Clinical Trials 295 7. Conclusions 296 Mark Joseph Mitton-Fry |
|
Chapter 16 | Capsid Assembly Modulators as Novel Antiviral Agents for the Treatment of Hepatitis B
Capsid Assembly Modulators as Novel Antiviral Agents for the Treatment of Hepatitis B1. Introduction 305 1.1 Hepatitis B Overview 305 1.2 Capsid Biology 306 2. Capsid Assembly Modulator Chemotypes 307 2.1 Heteroaryl Pyrimidines 307 2.2 Sulfonyl Carboxamides 309 2.3 Others 311 3. Mechanism of Action 312 4. In Vivo Preclinical Studies and Emerging Clinical Data with Capsid Assembly Modulators 314 5. Concluding Remarks 315 Scott D. Kuduk and Angela M. Lam |
|
Chapter 17 | Recent Advances Towards Rational Antibacterial Discovery: Addressing Permeation and Efflux
Recent Advances Towards Rational Antibacterial Discovery: Addressing Permeation and Efflux1. Introduction 319 2. New Mindsets In Antibacterial Development 321 2.1 Disparate Membrane Polarity in Gram-Negatives 321 2.2 Chemical Space and Structural Uniqueness of Gram-Negative Actives 322 2.3 Enhanced Antibacterial Potency 322 2.4 Early Consideration of Combinatorial Therapy 322 2.5 Development of Narrow-Spectrum Therapeutics 323 2.6 Non-Traditional Approaches to Antibacterial Development 323 3. Methods to Evaluate Antibacterial Activity 323 3.1 Chemical Modification of Cells 324 3.2 Genetic Modification of Cells 325 4. Methods to Determine Compound Permeation and Accumulation 325 4.1 Mass Spectrometry 326 4.2 Fluorescence 326 4.3 Electrophysiology and Liposome Swelling Assays 326 5. Recent Examples of Rational Approaches to Enhance Gram-Negative Accumulation 328 5.1 Sulfamoyladenosines 329 5.2 Oxazolidinones 330 5.3 Tetrahydropyran-Based Topoisomerase Inhibitors 332 5.4 Diverse Chemotype Analysis 333 6. Conclusion 334 Quentin P. Avila, Helen I. Zgurskaya, and Adam S. Duerfeldt |
|
Chapter 18 | Endogenous Allosteric Modulators of G Protein-Coupled Receptors: Implications in Drug Design
Endogenous Allosteric Modulators of G Protein-Coupled Receptors: Implications in Drug Design1. Introduction 343 2. Oligomers 344 3. Ions 348 4. Peptides 351 5. Amino Acids 352 6. Purinergic Nucleotides 353 7. Carbohydrates 353 8. Lipids 354 9. Metabolites of Orthosteric Ligands 355 10. Summary: Implications in Drug Design 357 Dario Doller |
|
Chapter 19 | Thinking Small and Dreaming Big: Medicinal Chemistry Strategies for Designing Optimal Antibody-Drug Conjugates (ADCs)
Thinking Small and Dreaming Big: Medicinal Chemistry Strategies for Designing Optimal Antibody-Drug Conjugates (ADCs)1. Introduction 363 2. Thinking Small: Optimization of the Linker-Payload 364 2.1 Advancing New Linker-Cleavage Mechanisms 364 2.2 Understanding the Released Species 367 2.3 Optimizing the Linker Stability 370 3. Dreaming Big: Optimization of the Bioconjugate 373 3.1 The Impact of the Linker-Payload on the Biophysical Properties of the ADC 373 3.2 The Impact of Conjugation Site on the Stability of the Linker Payload 375 4. Conclusions and Future Outlook 379 L. Nathan Tumey |
|
Chapter 20 | SILAC Proteomics in Drug Discovery
SILAC Proteomics in Drug Discovery1. Introduction 383 1.1 Overview 383 1.2 Proteomics Approaches to Understanding Biological Function 385 1.2.1 SILAC 385 1.2.2 Isobaric Tagging-Coupled Mass Spectrometry 385 2. SILAC Analysis Strategies 386 2.1 SILAC Labeling and Global Proteome Analysis in Cultured Cells 386 2.2 Application of SILAC to Analysis of Post-Translational Modifications and Protein Interaction Networks 387 2.3 SILAC Strategies for Whole Animal and Human Studies 392 3. SILAC Proteomics in Drug Discovery 393 3.1 Target Discovery and Pathway Biology 393 3.2 Compound Mechanism of Action 395 3.3 Biomarker Discovery 398 4. Limitations of SILAC 398 5. Conclusions 398 Thomas M. Graczyk, James P. Finn, and Ravi R. Iyer |
|
Chapter 21 | Aldehyde Oxidase Metabolism in Drug Discovery
Aldehyde Oxidase Metabolism in Drug Discovery1. Introduction 405 2. Extensive Metabolism Observed During Clinical Trials 406 3. Structure and Function of Aldehyde Oxidase 408 3.1 Structural and Mechanistic Aspects 408 3.2 Substrate Scope 409 4. Variation in Structure, Function and Distribution 410 5. Identifying and Predicting Aldehyde Oxidase Metabolism 411 6. Strategies to Attenuate Aldehyde Oxidase Metabolism 413 6.1 Androgen Receptor Antagonists 413 6.2 Toll-Like Receptor Antagonists 413 6.3 Zoniporide Derivatives 414 6.4 Phosphatidylinositol 3-Kinase Inhibitors 415 6.5 Mesenchymal—Epithelial Transition Factor Inhibitors 416 6.6 Deuterium Incorporation: VX-984 416 6.7 Tropomyosin-Related Kinase Inhibitors 417 7. Conclusion 417 Aaron C. Burns |
|
Chapter 22 | Repositioning Strategies that Target Remyelination for the Treatment of Multiple Sclerosis
Repositioning Strategies that Target Remyelination for the Treatment of Multiple Sclerosis1. Introduction 423 2. In Vitro Functional Screening of Remyelination 425 2.1 Phenotypic Assays of Remyelination 426 3. Targets and Repositioning Drugs for Remyelination 427 3.1 Muscarinic Antagonists 427 3.2 Dopamine Modulators 429 3.3 Kappa Opioid Receptor Agonists 431 3.4 Endocannabinoid Ligands 432 3.5 PDE7 Inhibitors 434 3.6 PPAR Receptor Agonists 434 3.7 Miscellaneous Targets and Drugs 435 4. Conclusion 437 Stefania Risso, Robert L. Hudkins, Peter H. Hutson, and Dmitri Leonoudakis |
|
Chapter 23 | Structure-Activity Relationship (SAR) Studies of Transient Receptor Potential (TRP) Channel Modulators
Structure-Activity Relationship (SAR) Studies of Transient Receptor Potential (TRP) Channel Modulators1. Introduction 443 2. TRP Channel Structural Features and Gating 444 2.1 General TRP Architecture 444 2.2 Specific Features of TRPV1, TRPA1, and TRPM8 445 2.3 TRP Channel Gating 447 2.4 Ligand Binding Domains of TRPV1, TRPA1, and TRPM8 447 3. Modulators of TRPV1, TRPA1, and TRPM8 449 3.1 Physiological Impacts of Modulating TRPV1, TRPA1, and TRPM8 449 3.2 Nonselective Natural TRP Channel Modulators 450 3.3 Nonselective Synthetic Modulators 453 3.4 Selective Synthetic Modulators 454 4. Conclusion 460 Christina M. LeGay and Darren J. Derksen |
|
Chapter 24 | Drug-Induced Liver Injury (DILI) Arising from Inhibition of Bile Acid Transport Proteins
Drug-Induced Liver Injury (DILI) Arising from Inhibition of Bile Acid Transport Proteins1. Introduction 465 2. BSEP Deficiency and DILI 466 3. Inhibition of BA Transport as a Causative Factor for DILI 467 4. Physicochemical Characteristics and Structure-Toxicity Relationships 470 4.1 Nontricyclic Antidepressants 473 4.2 Thiazolidinediones 473 4.3 Endothelial Receptor Antagonists (ERAs) 475 5. Prediction of DILI Risk 477 6. Conclusion 479 Michael D. Aleo, Deepak Dalvie, and Amit S. Kalgutkar |
|
Chapter 25 | Case History: Zurampic® (Lesinurad): A Selective Uric Acid Reabsorption Inhibitor for the Treatment of Hyperuricemia in Gout Patients
Case History: Zurampic® (Lesinurad): A Selective Uric Acid Reabsorption Inhibitor for the Treatment of Hyperuricemia in Gout Patients1. Introduction 485 2. Mechanisms of the Disease 486 3. Discovery of Lesinurad 488 4. Scale-up Process Development 489 5. Path to Regulatory Approval 490 6. Conclusion 492 Jean-Luc Girardet and Barry D. Quart |
|
Chapter 26 | Case History: Epidaza® (Chidamide): A Novel Oral Histone Deacetylase Inhibitor with Subtype Selectivity for Cancer Treatment
Case History: Epidaza® (Chidamide): A Novel Oral Histone Deacetylase Inhibitor with Subtype Selectivity for Cancer Treatment1. Introduction 497 2. Discovery of Chidamide 498 2.1 Identification of Chemical Scaffold Inhibiting HDACs 498 2.2 Medicinal Chemistry Efforts Aimed at the Discovery of New Selective HDAC Inhibitor 499 2.3 Multiplicity of Anticancer Mechanism 503 3. Preclinical Profiles of Chidamide 504 4. Clinical Development of Chidamide 506 4.1 A Phase I Clinical Study 506 4.2 Exploratory and Pivotal Phase II Clinical Studies on PTCL 508 5. Conclusions 510 Xian P. Lu, Zhi B. Li, Zhi Q. Ning, De S. Pan, Song Shan, Xia Guo, Hai X. Cao, Jin D. Yu, and Qian J. Yang |
|
Chapter 27 | New Chemical Entities Entering Phase III Trials in 2016
New Chemical Entities Entering Phase III Trials in 2016Information for 44 drugs in Phase III Trials Amy S. Lee, Adam J. Schrier, Salman Jabri, Nathan E. Wright, and Gregory T. Notte |
|
Chapter 28 | To Market, To Market--2016
To Market, To Market--20161. Atezolizumab (anticancer) 537 2. Beclabuvir (antiviral) 539 3. Bezlotoxumab (antibacterial) 541 4. Brivaracetam (epilepsy) 543 5. Brodalumab (psoriasis) 545 6. Crisaborole (atopic dermatitis) 547 7. Elbasvir (antiviral) 549 8. Etelcalcetide (secondary hyperthyroidism) 551 9. Eteplirsen (Duchenne muscular dystrophy) 553 10. Evogliptin (diabetes) 555 11. Gosogliptin (diabetes) 557 12. Grazoprevir (antiviral) 558 13. Ixekizumab (psoriasis) 560 14. Lifitegrast (dry eye disease) 563 15. Migalastat (Fabry disease) 565 16. Nusinersen (spinal muscular atrophy) 566 17. Obeticholic Acid (primary biliary cholangitis) 569 18. Obiltoxaximab (antibacterial) 571 19. Olaratumab (anticancer) 572 20. Olmutinib (anticancer) 574 21. Opicapone (Parkinson’s disease) 576 22. Pimavanserin (Parkinson’s disease) 578 23. Pitolisant (narcolepsy) 580 24. Reslizumab (asthma) 581 25. Rucaparib (anticancer) 583 26. Venetoclax (anticancer) 585 27. Velpatasvir (antiviral) 587 Catherine A. Bolger, T.G. Murali Dhar, Achal Pashine, Peter S. Dragovich, William Mallet, J. Robert Merritt, and Kevin M. Peese |