1391628-36-6Relevant articles and documents
Discovery of a novel class of potent HCV NS4B inhibitors: SAR studies on piperazinone derivatives
Kakarla, Ramesh,Liu, Jian,Naduthambi, Devan,Chang, Wonsuk,Mosley, Ralph T.,Bao, Donghui,Steuer, Holly M. Micolochick,Keilman, Meg,Bansal, Shalini,Lam, Angela M.,Seibel, William,Neilson, Sandra,Furman, Phillip A.,Sofia, Michael J.
, p. 2136 - 2160 (2014/04/03)
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 HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p- fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.
