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
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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, <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><sub>a</sub> 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