2. Academic Validation
  3. 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

  • J Med Chem. 2016 Nov 23;59(22):10228-10243. doi: 10.1021/acs.jmedchem.6b01234.
Wensheng Yu 1,  Ling Tong 1,  Bin Hu 2,  Bin Zhong 2,  Jinglai Hao 2,  Tao Ji 2,  Shuai Zan 2,  Craig A Coburn 3,  Oleg Selyutin 1,  Lei Chen 1,  Laura Rokosz 4,  Sony Agrawal 4,  Rong Liu 5,  Stephanie Curry 5,  Patricia McMonagle 5,  Paul Ingravallo 5,  Ernest Asante-Appiah 5,  Shiying Chen 6,  Joseph A Kozlowski 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway New Jersey 07065, United States.
  • 2 WuXi AppTec , 288 Fute Zhong Road, Shanghai, 200131, China.
  • 3 Department of Medicinal Chemistry, Merck Research Laboratories , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
  • 4 Department of in Vitro Pharmacology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 5 Department of Infectious Diseases, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 6 Department of PPDM, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 27792320 DOI: 10.1021/acs.jmedchem.6b01234
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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P0162
    HCV 抑制剂
    HCV
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