Discovery of a Silicon-Containing Pan-Genotype Hepatitis C Virus NS5A Inhibitor

We describe a study
leading to the discovery of compound 11, a pan-genotypic
hepatitis C virus (HCV) nonstructural
protein 5A (NS5A) inhibitor with excellent potency, metabolic stability,
and pharmacokinetics (PK). Compound 11 incorporating
a 4-silapiperidine group was discovered by further optimizing our
previous lead with a triethylsilyl moiety. It displayed great potency
against genotype 1 subtype a (GT1a), -1b, -2a, -3a, -4a, -5a, and
-6a with an EC50 range of 0.33–17 pM and improved
potency against the resistance-associated variant GT1a_M28T. Pharmacokinetics
(PK) study indicated that compound 11 has reasonable
PK exposures with a high liver distribution in preclinical animal
species (mouse, rat, and dog). The results of a 14 day repeat-dose
toxicity study identified the safety of compound 11.