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

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, <b>27</b>) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (<b>1</b>). Cell-based replicon potency was significantly improved through electronic modulation of the p<i>K</i>_a of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to <b>27</b>, a predicted low clearance compound in man. The preclinical profile of inhibitor <b>27</b> is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound