Discovery of a Novel Class of Potent HCV NS4B Inhibitors: SAR Studies on Piperazinone Derivatives

作者：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

来源：Journal of Medicinal Chemistry, 2014, 57(5): 2136-2160.

DOI：10.1021/jm4012643

HTS screening identified compound 2a (piper-azinone 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 la potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.

• 出版日期2014-3-13