Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease
Inhibitors Spanning the P2–P1′ Region
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Abstract
Herein,
novel hepatitis C virus NS3/4A protease inhibitors based
on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers
of an aryl acyl sulfonamide functionality in P1 are presented. The
P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly
beneficial in terms of inhibitory potency. Several inhibitors with <i>K</i><sub>i</sub>-values in the nanomolar range were developed
and included identification of promising P3-truncated inhibitors spanning
from P2–P1′. Of several different P2 capping groups
that were evaluated, a preference for the sterically congested Boc
group was revealed. The inhibitors were found to retain inhibitory
potencies for A156T, D168V, and R155K variants of the protease. Furthermore,
in vitro pharmacokinetic profiling showed several beneficial effects
on metabolic stability as well as on apparent intestinal permeability
from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl
side chain
