当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants.

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).

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Yu W,Tong L,Hu B,Zhong B,Hao J,Ji T,Zan S,Coburn CA,Selyutin O,Chen L,Rokosz L,Agrawal S,Liu R,Curry S,McMonagle P,Ingravallo P,Asante-Appiah E,Chen S,Kozlowski JA

doi

10.1021/acs.jmedchem.6b01234

subject

Has Abstract

pub_date

2016-11-23 00:00:00

pages

10228-10243

issue

22

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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