2. Academic Validation
  3. Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates

  • ACS Med Chem Lett. 2017 Jan 31;8(2):251-255. doi: 10.1021/acsmedchemlett.6b00479.
Pan Li 1,  Warren Dorsch 1,  David J Lauffer 1,  Darius Bilimoria 1,  Nathalie Chauret 2,  John J Court 1,  Sanjoy Kumar Das 2,  Francois Denis 2,  Nagraj Mani 1,  Suganthini Nanthakumar 1,  Olivier Nicolas 2,  B Govinda Rao 1,  Steven Ronkin 1,  Subajini Selliah 2,  Rebecca S Shawgo 1,  Ralph Stearns 1,  Qing Tang 1,  Nathan D Waal 1,  Jeremy Green 1
Affiliations

Affiliations

  • 1 Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
  • 2 Vertex Pharmaceuticals (Canada) Incorporated , 275 Boulevard Armand Frappier, Laval, Quebec H7 V 4A7, Canada.
PMID: 28197321 DOI: 10.1021/acsmedchemlett.6b00479
Abstract

Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the Antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by 12f, provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships, in vitro ADME characterization, and in vivo evaluation of this novel series are discussed.

Keywords

Lomibuvir; NS5B; antiviral activity; hepatitis C; non-nucleoside; polymerase.

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