Reviews: 2021 Medicinal Chemistry Reviews

Ref. n°: REV2021

Volume :	56
Editor-In-Chief :	Joanne J. Bronson

Medicinal Chemistry Reviews is an outstanding 965 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

Chapter 1	What I Did on My Summer Vacation and Molecules That Broke My Heart John E. Macor
Chapter 2	Preclinical Targets for Promoting Remyelination via OOPC Differentiation Preclinical Targets for Promoting Remyelination via OOPC Differentiation 1. Introduction 23 2. Oligodendrocyte Precursor Cell Differentiation Targets 26 2.1 GPR17 26 2.2 Cholesterol Biosynthesis and Homeostasis 28 2.2.1 LXR family 28 2.2.2 EBP 30 2.3 RXR family 31 2.4 VDR 33 2.5 CXCR4 and CXCR7 34 2.6 ERK1/2 36 2.7 TNFR 1 and 2 38 2.8 HDAC1/2 and 3 39 3. Summary 41 Robin J. Prince, Ryan W. Evans
Chapter 3	Activation of Autophagy for the Treatment of Neurodegenerative Diseases Activation of Autophagy for the Treatment of Neurodegenerative Diseases 1. Introduction and Background 49 1.1 Autophagy in CNS disorders 50 1.2 Regulation of Autophagy 52 1.3 PINK1/Parkin Modulates Mitochondrial Fitness 54 2. Activation via mTOR/PI3K Pathway 56 2.1 Allosteric Binding by Immunophilin Natural Products 56 2.2 Optimization of ATP-Competitive mTOR/PI3K Inhibitors 57 3. Therapeutic Activation of PINK1/Parkin to Regulate Mitophagy 64 3.1 Direct Activation of PINK1 64 3.2 USP30 Inhibitors 65 3.3 Novel Compounds and Emerging Targets 66 4. Conclusions and Future Outlook 69 Bhaumik A. Pandya, Rebecca Aron
Chapter 4	Recent Advances in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors Recent Advances in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors 1. Introduction 79 2. Small-Molecule Inhibitors 81 2.1 Inhibition of PCSK9 mRNA Translation 81 2.2 Reduction in PCSK9 Secretion 82 2.2.1 C-terminal Domain Interaction 82 2.2.2 Unknown Mechanisms 83 2.3 Blocking the PCSK9-LDLR Interaction 84 3. Peptide Inhibitors of the PCSK9-LDLR Interaction 88 3.1 Cyclic Peptides 88 3.2 Linear Peptides 93 3.3 Peptidomimetics 95 4. Conclusion 96 Chris Limberakis, David W. Piotrowski
Chapter 5	Advances in Small-Molecule Heart Failure Therapy Advances in Small-Molecule Heart Failure Therapy 1. Introduction and Overview 103 2. Heart Failure Pathophysiology, Medical Significance, and Challenges 104 2.1 Overview of HF (HFpEF vs. HFrEF) Pathophysiology 104 2.2 Evaluation and Therapeutic Strategies 105 2.3 Current Evidence-Based Pharmacologic Strategies 106 3. New Cornerstone HF Therapies 108 3.1 AT1 Antagonists and Neprilysin (NEP) Inhibitors (ARNI) 108 3.2 Sodium-Glucose Co-Transporter-2 (SGLT2) 110 4. Medicinal Chemistry and Pharmacologic Evaluation of Potential New Therapies 112 4.1 Dual AT1 Antagonists and Neprilysin (NEP) Inhibitors 112 4.2 G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors 113 4.3 ASK1 Inhibitors 114 4.4 ATTR Stabilizer 116 5. Sarcomere Modulator 116 6. Conclusions and Future Directions 118 Kyle B. Mott, J. Phillip Bowen, Maan Jokhadar
Chapter 6	Advances in Pharmacological Targeting of the Complement System Advances in Pharmacological Targeting of the Complement System 1. Introduction 127 1.1 The Complement System 127 1.2 Complement-Associated Diseases in Humans 129 2. Discovery and Development of Complement-Targeting Therapeutics 131 2.1 C1 Inhibitors 131 2.2 C2 Inhibitors 133 2.3 Inhibitors of MASPs 134 2.4 Factor B Inhibitors 135 2.5 Factor D Inhibitors 136 2.6 Properdin Inhibitors 138 2.7 C3 Inhibitors 139 2.8 C3aR Modulators 140 2.9 Modulators of C3b and Related Complement Proteins 141 2.10 C5 Inhibitors 141 2.11 C5a Inhibitors 144 2.12 C5aR Antagonists 145 2.13 C5L2 Modulators 147 2.14 Inhibitors of the Terminal Pathway and MAC 148 3. Targeting Complement for the Treatment of COVID-19 148 4. Conclusion 149 Penglie Zhang, Shijie “Chris” Li
Chapter 7	Systemic and Intestinally Restricted JAK Inhibitors in IBD Systemic and Intestinally Restricted JAK Inhibitors in IBD 1. Background Biology of Ulcerative Colitis and Crohn’s Disease 159 2. Systemic JAK Inhibitors in Clinical Trials for Ulcerative Colitis 161 3. Systemic JAK Inhibitors in Clinical Trials for Crohn’s Disease 163 4. Summary of Systemic JAK Inhibitors’ Efficacy and Safety 164 5. Intestinally Restricted JAK Inhibitors for IBD 165 5.1 Profile of Intestinally Restricted pan-JAK Imidazopyrrolopyridine Inhibitors 165 5.2 Preclinical Profile of Intestinally Restricted Izencitinib (TD-1473) 167 5.3 Izencitinib Results in Ulcerative Colitis Clinical Trials 171 6. Conclusion 173 Kristi A. Leonard, Jennifer D. Venable
Chapter 8	Small-Molecule Inhibitors of PD-L1 Small-Molecule Inhibitors of PD-L1 1. Introduction 181 2. Structural Basis of Inhibiting PD-L1 182 3. Discovery of Small-Molecule PD-L1 Inhibitors 186 4. Clinical Development Update 192 5. Conclusion 193 Yibin Zeng, Shijie “Chris” Li, Kathleen Sullivan, Penglie Zhang
Chapter 9	Targeting EGFR and HER2: Past, Present, and Future Targeting EGFR and HER2: Past, Present, and Future 1. Introduction: The EGFR Family and Their Activating Mutations 203 2. Approved EGFR and HER2 Therapies 205 2.1 First- and Second-Generation EGFR and HER2 TKIs 205 2.2 The T790M Mutation and Third- Generation EGFR TKIs 208 3. The Next Frontiers 209 3.1 Primary Activating Mutations Without Approved Therapies 209 3.2 Alternative Strategies 215 3.3 Resistance Mechanisms to Third- Generation EGFR TKIs 219 4. Future Directions and Conclusions 221 Emily J. Hanan, Marian C. Bryan
Chapter 10	Recent Advances in Small-Molecule PARP Family Inhibitors Recent Advances in Small-Molecule PARP Family Inhibitors 1. Introduction to the PARP Family of Enzymes 231 1.1 The 17 Members of the PARP Family of Enzymes 231 1.2 Approaches to Study PARP Enzyme Target Engagement 234 2. PARP1 and PARP2 236 2.1 A Brief History of PARP1 Inhibitors 236 2.2 New PARP1 Inhibitors Entering Clinical Trials 236 2.3 PROTACs Targeting PARP1 and PARP2 238 3. The Tankyrases (PARP5a/5b) 240 3.1 Introduction to the Tankyrases 240 3.2 Current Clinical Candidates Targeting Tankyrase 241 3.3 New Preclinical Tankyrase Inhibitors 242 4. PARP6 244 5. PARP7 245 6. PARP10 246 7. PARP11 247 8. PARP14 247 8.1 Catalytic Reversible Inhibitors 247 8.2 PARP14 Degrader 249 8.3 PARP14 Macrodomain Binders 249 9. Screening of an NAD+-Mimicking DNA-Encoded Library 250 10. Conclusions 251 Jeffrey W. Johannes, Avipsa Ghosh, Nicholas R. Perl, Melissa M. Vasbinder
Chapter 11	Direct-Acting Small-Molecule Antivirals for the Treatment of COVID-19 Direct-Acting Small-Molecule Antivirals for the Treatment of COVID-19 1. Introduction 269 2. Inhibitors of RNA-Dependent RNA Polymerase (RdRp) 270 2.1 Strand-Terminating Nucleoside Inhibitors 271 2.2 RNA-Modifying (Mutagenic) Nucleoside Inhibitors 274 2.3 Non-Nucleoside Inhibitors 277 3. Inhibitors of Main Protease (Mpro) 277 4. Inhibitors of Papain-Like Protease (PLpro) 280 5. Other Targets 281 6. Conclusion 282 Britton K. Corkey, John P. Bilello, Sheila M. Zipfel, Jason K. Perry
Chapter 12	Plasmodium Kinase Inhibitors as Potential Multistage Active Antimalarials Plasmodium Kinase Inhibitors as Potential Multistage Active Antimalarials 1. Introduction 295 2. Kinases and the Plasmodium Kinome 298 3. Inhibitors of Plasmodium Protein Kinases 299 3.1 Inhibitors of P. falciparum cGMP-Dependent Protein Kinase (PfPKG) 299 3.2 Inhibitors of P. falciparum Cyclin- Dependent-Like Kinase 3 (PfCLK3) 303 3.3 Other Notable Inhibitors of Plasmodium Protein Kinases 304 4. Inhibitors of Plasmodium Lipid Kinases 306 4.1 Overview of Plasmodium Lipid Kinases and Their Inhibitors 306 4.2 Inhibitors of P. falciparum Phosphatidylinositol 4-Kinase (PfPI4K) 306 5. Challenges and Opportunities for the Development of Multistage Plasmodium Kinase Inhibitors 310 6. Conclusions 313 John G. Woodland, Kelly Chibale
Chapter 13	Cysteine Protease Inhibitors for Infectious Diseases Cysteine Protease Inhibitors for Infectious Diseases 1. Introduction 321 1.1 Classifications 323 2. Cysteine Proteases in Parasitic Infectious Diseases 323 2.1 Human African Trypanosomiasis (Rhodesain) 323 2.2 Leishmaniasis (Cathepsin L-like) 325 2.3 Chagas Disease (Cruzain) 327 2.4 Malaria (Falcipain) 329 2.5 Toxoplasmosis (Cathepsin) 332 3. Conclusion 334 Courtney Fu, Gabriella I. D. Cooper, Lori Ferrins
Chapter 14	Glycoside Hydrolases as Therapeutic Targets for CNS Indications Glycoside Hydrolases as Therapeutic Targets for CNS Indications 1. Glycoside Hydrolases Overview 343 2. The O-GlcNAc Pathway and OGA 345 3. Lysosomal Function and GCase 347 4. OGA and Alzheimer’s Disease 348 5. Glycoside Hydrolases and Parkinson’s Disease 350 6. Small-Molecule OGA Inhibitors 352 7. GCase Activators 356 7.1 Pharmacological Chaperone Approaches 356 7.2 Direct Activation 358 8. Conclusion 358 Jinkuk Choi, Kevin Guckian, Heike Hering, Nathan E. Genung
Chapter 15	SLC Transporters: Portals for Therapeutic Opportunity SLC Transporters: Portals for Therapeutic Opportunity 1. Introduction 367 2. Overview of SLC Transporters 369 3. Examples of Successful SLC Therapies 373 4. SLCs Across Human Disease 375 4.1 Diabetes, Cardiovascular, and Metabolic Diseases 375 4.2 Immune and Inflammatory Diseases 376 4.3 Immune Oncology 376 5. Current Challenges and Future Opportunities 378 Nicholas B. Last, Eitan Hoch
Chapter 16	Recent Developments in Targeting “Undruggable” SH3 Domains Recent Developments in Targeting “Undruggable” SH3 Domains 1. Introduction 389 2. Protein-Protein Interactions and SH3 Domains 390 2.1 Protein-Protein Interactions in Biology 390 2.2 Protein-Protein Interactions as Challenging, Non-Traditional Therapeutic Targets 392 2.3 SH3 Domain Structure and Function 395 2.4 SH3 Domains as Potential Therapeutic Targets 395 3. Recent Developments in Targeting SH3 Domains 395 3.1 Peptide Ligands 396 3.2 Peptide-Based or “Peptoid” Ligands 398 3.3 Small-Molecule Ligands 399 3.4 Organic-Inorganic Hybrid Ligands 403 4. Conclusions 405 Ellen Lillian Swan, Stephanie Jayne, Simon Matthew Pyke
Chapter 17	Reaction Development for DNA-Encoded Library Technology: Expanding the Toolkit on DNA Chemistry Reaction Development for DNA-Encoded Library Technology: Expanding the Toolkit on DNA Chemistry 1. Introduction 414 2. Background 414 2.1 Triazines 414 2.2 Amides 415 2.3 Sulfonamides 415 3. Heterocyclic Ring Formation on-DNA 416 4. Cross Couplings 419 5. Macrocyclizations on-DNA 421 6. Hydrogenation 424 7. Photoredox 425 8. Biocatalysis 429 9. Alternative Strategies for DNA-Encoded Library Synthesis 430 9.1 Controlled Pore Glass (CPG) Solid Phase Approach 430 9.2 Reversible Immobilization on DEAE Sepharose Beads 432 9.3 Reversible Adsorption to Solid Support (RASS) Approach 432 9.4 Amphiphilic Polymer-Facilitated Transformations under Anhydrous Conditions (APTAC) Approach 435 10. Future Directions 435 Adam Csakai, Yun Ding, Melissa C. Grenier-Davies, Lisa A. Marcaurelle, Ann M. Rowley
Chapter 18	Escape from Protacs®: Recent Developments in Protein Degradation With Small-Molecule Glues Escape from Protacs®: Recent Developments in Protein Degradation With Small-Molecule Glues 1. Introduction 443 2. Tools for Molecular Glue Drug Discovery 445 3. CRBN-Based Molecular Glues 448 4. Considerations for the Discovery of Molecular Glue Candidates 450 5. Emerging Non-CRBN-Based Molecular Glue 453 6. Future Directions and Conclusions 456 Jennifer R. Riggs,* Deborah S. Mortensen, Thomas Clayton, Christoph W. Zapf
Chapter 19	Glossary and Tutorial of Xenobiotic Metabolism Terms Used During Small-Molecule Drug Discovery and Development Glossary and Tutorial of Xenobiotic Metabolism Terms Used During Small-Molecule Drug Discovery and Development Due to the length of this chapter, only the Abstract and Alphabetical List of Terms are being included in the print version. The chapter in its entirety can be found in the on-line version (available to members at the ACS MEDI Division website https://www.acsmedchem.org/) and in the original publication by Paul Erhardt et al. in Pure Appl. Chem. 2021, 93, 273-403. Alphabetical List of Terms 465 Introduction 471 Definitions with Structural Examples and Tutorials 476 Membership of Sponsoring Bodies 639 Acknowledgments 640 Appendices 641 Paul Erhardt,* Kenneth Bachmann, Donald Birkett, Michael Boberg, Nicholas Bodor, Gordon Gibson, David Hawkins, Gabrielle Hawksworth, Jack Hinson, Daniel Koehler, Brian Kress, Amarjit Luniwal, Hiroshi Masumoto, Raymond Novak, Phillip Portoghese, Jeffrey Sarver, M. Teresa Serafini, Christopher Trabbic, Nico Vermeulen, and Steven Wrighton
Chapter 20	New Chemical Entities Entering Phase III Trials in 2020 Matthew L. Condakes, Alec H. Christian, Anna E. Hurtley, David W. Lin, Rhiannon Thomas-Tran, Karl T. Haelsig
Chapter 21	To Market, to Market—2020: Small Molecules To Market, to Market—2020: Small Molecules 1. Abametapir (infectious diseases; head lice) 693 2. Almonertinib (anticancer; non-small-cell lung cancer) 695 3. Artesunate (infectious diseases; malaria) 697 4. Avapritinib (anticancer; gastrointestinal stromal tumor) 700 5. Bempedoic acid (cardiovascular; hypercholesterolemia and atherosclerotic cardiovascular disease) 702 6. Bencycloquidium bromide (immunology and inflammation; allergic rhinitis) 705 7. Berotralstat (genetic diseases; hereditary angioedema) 707 8. Borofalan (10B) (anticancer; head and neck cancer) 709 9. Capmatinib (anticancer; non-small-cell lung cancer) 711 10. Carrimycin (infectious diseases; upper respiratory infection) 713 11. Cedazuridine (anticancer; myelodysplastic syndromes and chronic myelomonocytic leukemia) 714 12. Centhaquine (cardiovascular; hypovolemic shock) 717 13. Clascoterone (immunology and inflammation; acne) 719 14. Danoprevir (infectious diseases; hepatitis C) 721 15. Daprodustat (blood disorders; anemia) 724 16. Delgocitinib (immunology and inflammation; atopic dermatitis) 727 17. Dotinurad (blood disorders; gout and hyperuricemia) 729 18. Enarodustat (blood disorders; anemia) 732 19. Ensartinib (anticancer; non-small-cell lung cancer) 735 20. Filgotinib (immunology and inflammation; rheumatoid arthritis) 737 21. Fostemsavir (infectious diseases; human immunodeficiency virus type 1) 740 22. Levonadifloxacin and alalevonadifloxacin (infectious diseases; acute bacterial skin and skin structure infections) 743 23. Lonafarnib (genetic diseases; Hutchinson Gilford progeria syndrome) 746 24. Lurbinectedin (anticancer; small-cell lung cancer) 748 25. Monomethyl fumarate (CNS; multiple sclerosis) 751 26. Nifurtimox (infectious diseases; Chagas disease) 754 27. Oliceridine (CNS; analgesic) 757 28. Osilodrostat (rare diseases; Cushing’s disease) 759 29. Ozanimod (CNS; multiple sclerosis) 762 30. Pemigatinib (anticancer; cholangiocarcinoma) 764 31. Pralsetinib (anticancer; non-small-cell lung cancer) 766 32. Ravidasvir (infectious diseases; hepatitis C) 768 33. Remdesivir (infectious diseases; coronavirus disease 2019) 771 34. Rimegepant (CNS; migraine) 774 35. Ripretinib (anticancer; gastrointestinal stromal tumor) 776 36. Risdiplam (CNS; spinal muscular atrophy) 778 37. Selpercatinib (anticancer; non-small-cell lung cancer and thyroid cancer) 781 38. Selumetinib (genetic diseases; neurofibromatosis type 1) 783 39. Sofpironium bromide (rare diseases; primary axillary hyperhidrosis) 785 40. Tazemetostat (anticancer; epithelioid sarcoma) 787 41. Tepotinib (anticancer; non-small-cell lung cancer) 789 42. Tirbanibulin (anticancer; actinic keratosis) 792 43. Triheptanoin (genetic diseases; long-chain fatty acid oxidation disorders) 794 44. Tucatinib (anticancer; HER2-positive breast cancer) 796 Marie-Gabrielle Braun, Georgette Castanedo, Samantha A. Green, Mingshuo Zeng, Joseph Carpenter, Antonella Converso, Izzat T. Raheem, Anthony J. Roecker, Akshay A. Shah, Laurent Debien, T. G. Murali Dhar, Lauren M. Holder, J. Robert Merritt, Kevin M. Peese, Denise C. Grünenfelder, Julian C. Lo
Chapter 22	To Market, to Market—2020: Macromolecular Therapeutics Nicholas J. Agard, Peter S. Dragovich, Ryan L. Kelly, Shion A. Lim, Allison M. Beal, Ian Moench, Anna M. Gram, Pei-Pei Kung, Daša Lipovšek

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Reviews: 2021 Medicinal Chemistry Reviews

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