Current Drug Synthesis

ISBN-13: 9781119847250 / Angielski / Twarda / 2022 / 350 str.

Jie Jack Li

Spis treści

Preface xiContributing Authors xiiiPart I Infectious Disease Drugs 1Chapter 1 Relebactam (Recarbrio), A ß-Lactamase Inhibitor for the Treatment of cIAI/cUTI/HABP/ VABP 31 Background 32 Pharmacology 53 Structure-Activity Relationship (SAR) 64 Pharmacokinetics and Drug Metabolism 95 Efficacy and Safety 106 Syntheses 107 Summary 148 References 14Chapter 2 Vaborbactam (in Combination with Meropenem as Vabomere), a Non-ß-Lactam ß-Lactamase Inhibitor for Treatment of Complicated Urinary Tract Infections and Pyelonephritis 171 Background 172 Discovery Medicinal Chemistry 213 Vaborbactam/Vabomere Clinical Trials 274 Vaborbactam Medicinal Chemistry Synthesis 295 Vaborbactam Process Chemistry Synthesis 306 Conclusions 377 References 38Chapter 3 Baloxavir Marboxil (Xofluza), A Cap-Dependent Endonuclease Inhibitor for Treating Influenza 411 Background 412 Mechanism of Action 433 Structure-Activity Relationship 454 Pharmacokinetics and Drug Metabolism 495 Efficacy and Safety 506 Syntheses 507 Summary 548 References 54Chapter 4 Process Chemistry Development of the HIV Protease Inhibitor Drug Kaletra: A Mixture of Ritonavir and Lopinavir 571 Background 582 Ritonavir Portion of Kaletra Synthesis 583 Discovery Synthesis of the Ritonavir Core 604 Discovery Synthesis of Ritonavir Wing Pieces 635 Large-Scale Process Chemistry Synthesis of the Ritonavir Core 656 Large-Scale Syntheses of the 5-Hydroxymethyl Thiazole Wing Portion 697 The Large-Scale Coupling of the Thiazole Wing Pieces to the Core 708 Lopinavir Portion of Kaletra-- Discovery Synthesis and Process Development 729 Discovery Synthesis of Lopinavir 7310 Discovery Synthesis of Wing Pieces 7411 Process Improvements to the Wing Pieces 7612 Optimization of Lopinavir Synthesis with Intermediates 7813 Conclusions 8114 References 81Chapter 5 Eravacycline (Xerava), A Novel and Completely Synthetic Fluorocycline Antibiotic 851 Background 852 Pharmacology 893 Structure-Activity Relationship (SAR) 914 Pharmacokinetics and Drug Metabolism 935 Efficacy and Safety 936 Syntheses 937 Summary 988 References 99Chapter 6 Albuvirtide (Aikening), A gp41 Analog as an HIV-1 Fusion Inhibitor 1011 Background 1012 Pharmacology 1023 Structure-Activity Relationship (SAR) 1064 Pharmacokinetics and Drug Metabolism 1075 Efficacy and Safety 1106 Syntheses 1127 Summary 1148 References 115Part II Cancer Drugs 119Chapter 7 Darolutamide (Nubeqa): An Androgen Receptor Antagonist for Treating Nonmetastatic, Castration-Resistant 1211 Background 1212 Pharmacology 1243 Structure-Activity Relationship (SAR) 1264 Pharmacokinetics and Drug Metabolism 1325 Efficacy and Safety 1346 Syntheses 1357 The Future 1378 References 138Chapter 8 Venetoclax (Venclexta): A BCL-2 Antagonist for Treating Chronic Lymphocytic Leukemia 1431 Background 1432 Pharmacology 1443 Structure-Activity Relationship (SAR) 1474 Pharmacokinetics and Drug Metabolism 1535 Efficacy and Safety 1546 Syntheses 1557 Summary 1608 References 161Chapter 9 Osimertinib (Tagrisso), A Potent and Selective Third-Generation EGFR Inhibitor for the Treatment of Both Sensitizing and T790M-Resistance Mutations 1651 Background 1652 Pharmacology 1673 Structure-Activity Relationship (SAR) 1704 Pharmacokinetics and Drug Metabolism 1735 Efficacy and Safety 1746 Syntheses 1757 Summary 1808 References 180Chapter 10 Sotorasib (LUMAKRA), An Irreversible Covalent Inhibitor of KRASG12C 1831 Background 1832 Pharmacology 1843 Structure-Activity Relationship (SAR) 1864 Pharmacokinetics and Drug Metabolism 1915 Efficacy and Safety 1916 Syntheses 1927 Summary 1968 References 196Chapter 11 Lorlatinib (Lorbrena), An ALK Inhibitor for Treating NSCLC 2011 Background 2012 Pharmacology 2033 Structure-Activity Relationship (SAR) 2054 Pharmacokinetics and Drug Metabolism 2105 Efficacy and Safety 2116 Syntheses 2137 Summary 2268 References 227Chapter 12 Niraparib (Zejula) A Small Molecule, PARP1/2 Inhibitor for Treating Breast, Ovarian, and Pancreatic Cancers 2312 Pharmacology 2353 Structure-Activity Relationship (SAR) 2384 Pharmacokinetics and Drug Metabolism 2435 Efficacy and Safety 2436 Syntheses 2447 Summary 2488 References 248Chapter 13 Selinexor (Xpovio), An XPO1 Inhibitor and a New Class of Therapeutics for Treating Multiple Myeloma 2531 Exportin1 (XPO1) 2532 Overview of Multiple Myeloma 2553 Development of Selinexor 2564 Pharmacology and Mechanism 2575 Pharmacokinetics, Pharmacodynamics and Drug Metabolism 2586 Efficacy and Safety 2597 Syntheses 2598 Summary and Future 2629 References 262Part III Cns Drugs 265Chapter 14 Sage 217 (Zuranolone) for Treating Major of Depressive Disorder2671 Background 2672 Pharmacology 2703 Structure-Activity Relationship (SAR) 2724 Pharmacokinetics and Drug Metabolism 2795 Efficacy and Safety 2806 Syntheses 2817 Summary 2828 References 283Chapter 15 Risdiplam (Evrysdi), A Small Molecule, SMN2-directed RNA Splicing Modifier for Treating Spinal Muscular Atrophy 2871 Background 2872 Pharmacology 2893 Structure-Activity Relationship (SAR) 2904 Pharmacokinetics and Drug Metabolism 2975 Efficacy and Safety 2976 Syntheses 2987 Summary 3008 References 301Part IV Miscellaneous Drugs 305Chapter 16 Esaxerenone (Minnebro), An Oral, Non-steroidal, Selective Mineralocorticoid Receptor Blocker for the Treatment of Essential Hypertension3071 Background 3072 Pharmacology 3103 Structure-Activity Relationship (SAR) 3114 Pharmacokinetics and Drug Metabolism 3135 Efficacy and Safety 3156 Syntheses 3167 Summary 3208 References 321Chapter 17 Voclosporin (Lupkynis), A Macrocyclic Peptide Inhibitor of Calcineurin for the Treatment of Lupus Nephritis 3231 Background 3232 Pharmacology 3263 Structure-Activity Relationship (SAR) 3264 Pharmacokinetics and Drug Metabolism 3295 Efficacy and Safety 3316 Syntheses 3337 References 336Chapter 18 Computational-Aided Drug Design 3391 Background 3392 Structure-based Drug Design (SBDD) 3413 Ligand-based Drug Design (LBDD) 3524 Summary 3615 References 362Index 373

O autorze

Jie Jack Li, PhD, is the CSO of GenHouse Bio. Previously, he was VP of Discovery Chemistry at ChemPartner, an Associate Professor of Chemistry at the University of San Francisco and a Medicinal Chemist at Pfizer and Bristol-Myers Squibb. He has authored or edited over 30 books, including Medicinal Chemistry for Practitioners published by Wiley in 2020.