2 research outputs found
Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)
Combinations of direct acting antivirals (DAAs) that
have the potential
to suppress emergence of resistant virus and that can be used in interferon-sparing
regimens represent a preferred option for the treatment of chronic
HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside
inhibitors of HCV NS5B polymerase that inhibit replication in replicon
systems. Herein, we report the late-stage optimization of indole-based
inhibitors, which began with the identification of a metabolic liability
common to many previously reported inhibitors in this series. By use
of parallel synthesis techniques, a sparse matrix of inhibitors was
generated that provided a collection of inhibitors satisfying potency
criteria and displaying improved in vitro ADME profiles. āCassetteā
screening for oral absorption in rat provided a short list of potential
development candidates. Further evaluation led to the discovery of
the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated
antiviral activity in patients chronically infected with genotype
1 HCV
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><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