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.

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.

• Authors: Pierre L Beaulieu, 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 23 Pg. 10130-43 (Dec 11 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25393851 (Publication Type: Journal Article)

Chemical References

• (E)-3-(4-((1-((2-(5-chloro-pyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino)-cyclobutanecarbonyl)-amino)-2-ethoxy-phenyl)-acrylic acid
• Acrylates
• Antiviral Agents
• Cinnamates
• Enzyme Inhibitors
• Indoles
• Viral Nonstructural Proteins
• NS-5 protein, hepatitis C virus
• RNA-Dependent RNA Polymerase

Topics

• Acrylates (chemical synthesis, metabolism, pharmacokinetics)
• Animals
• Antiviral Agents (chemical synthesis, metabolism, pharmacology)
• Cinnamates (chemical synthesis, metabolism, pharmacokinetics)
• Dogs
• Enzyme Inhibitors (chemical synthesis, metabolism, pharmacokinetics)
• Hepatitis C, Chronic
• Humans
• Indoles (chemical synthesis, metabolism, pharmacokinetics)
• Macaca mulatta
• RNA-Dependent RNA Polymerase (antagonists & inhibitors)
• Rats
• Structure-Activity Relationship
• Viral Nonstructural Proteins (antagonists & inhibitors)