874676-60-5Relevant articles and documents
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
Beaulieu, Pierre L.,Anderson, Paul C.,Bethell, Richard,B?s, Michael,Bousquet, Yves,Brochu, Christian,Cordingley, Michael G.,Fazal, Gulrez,Garneau, Michel,Gillard, James R.,Kawai, Stephen,Marquis, Martin,McKercher, Ginette,Poupart, Marc-André,Stammers, Timothy,Thavonekham, Bounkham,Wernic, Dominik,Duan, Jianmin,Kukolj, George
, p. 10130 - 10143 (2015/02/05)
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.
