2. Academic Validation
  3. Discovery of BI 207524, an indole diamide NS5B thumb pocket 1 inhibitor with improved potency for the potential treatment of chronic hepatitis C virus infection

Discovery of BI 207524, an indole diamide NS5B thumb pocket 1 inhibitor with improved potency for the potential treatment of chronic hepatitis C virus infection

  • J Med Chem. 2014 Dec 11;57(23):10130-43. doi: 10.1021/jm501532z.
Pierre L Beaulieu 1,  Paul C Anderson,  Richard Bethell,  Michael Bös,  Yves Bousquet,  Christian Brochu,  Michael G Cordingley,  Gulrez Fazal,  Michel Garneau,  James R Gillard,  Stephen Kawai,  Martin Marquis,  Ginette McKercher,  Marc-André Poupart,  Timothy Stammers,  Bounkham Thavonekham,  Dominik Wernic,  Jianmin Duan,  George Kukolj
Affiliations

Affiliation

  • 1 Boehringer Ingelheim (Canada) Ltd. , Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
PMID: 25393851 DOI: 10.1021/jm501532z
Abstract

The development of interferon-free regimens for the treatment of chronic HCV Infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with Other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate Antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the PKA of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12474
    HCV NS5B 聚合酶抑制剂
    HCV
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