Discovery of a novel class of potent HCV NS4B inhibitors: SAR studies on piperazinone derivatives.

摘要: HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the nonstructural protein NS4B. Extensive SAR were performed around and amide function C-3/C-6 cis stereochemistry of core essential for activity. A 10-fold increase in GT-1 potency was observed when chiral phenylcyclopropyl side chain replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing C-6 nonpolar hydrophobic 67 phenyl (95) did not diminish potency. heterocyclic thiophene (103) an isoxazole (108) incorporated isosteric replacements (95), resulting significant improvement GT-1b 1a However, piperazonone class compounds lacks GT-2 activity and, consequently, pursued further into development.