title: Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants.
abstract: The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-associated variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, we now describe the discovery of a novel series of chromane containing NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the phenyl group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivatives as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors, such as compounds 14 and 25-28, with significantly improved potency against resistance-associated variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compound 14 also showed reasonable PK exposures in preclinical species (rat and dog).
authors: Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.
authors: Wensheng
authors: W
authors: Yu
authors: Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.
authors: Ling
authors: L
authors: Tong
authors: WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.
authors: Bin
authors: B
authors: Hu
authors: WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.
authors: Bin
authors: B
authors: Zhong
authors: WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.
authors: Jinglai
authors: J
authors: Hao
authors: WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.
authors: Tao
authors: T
authors: Ji
authors: WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.
authors: Shuai
authors: S
authors: Zan
authors: Department of Medicinal Chemistry, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Craig A
authors: CA
authors: Coburn
authors: Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.
authors: Oleg
authors: O
authors: Selyutin
authors: Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.
authors: Lei
authors: L
authors: Chen
authors: Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Laura
authors: L
authors: Rokosz
authors: Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Sony
authors: S
authors: Agrawal
authors: Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Rong
authors: R
authors: Liu
authors: Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Stephanie
authors: S
authors: Curry
authors: Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Patricia
authors: P
authors: McMonagle
authors: Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Paul
authors: P
authors: Ingravallo
authors: Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Ernest
authors: E
authors: Asante-Appiah
authors: Department of PPDM, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors: Shiying
authors: S
authors: Chen
authors: Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.
authors: Joseph A
authors: JA
authors: Kozlowski
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects*; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002839:Chromans; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase