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)
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Abstract
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. “Cassette”
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