Design and synthesis of imidazole N-H substituted amide prodrugs as inhibitors of hepatitis C virus replication

作者:Zong Xi; Cai Jin*; Chen Junqing; Wang Peng; Zhou Gaoxin; Chen Bo; Li Wei; Ji Min
来源:Bioorganic & Medicinal Chemistry Letters, 2015, 25(16): 3147-3150.
DOI:10.1016/j.bmcl.2015.06.006

摘要

Twenty-five novel imidazole N-H substituted Daclatasvir (BMS-790052, DCV) analogues (8a-8y) were designed and synthesized as potential prodrugs. Structure modifications were performed in order to improve potency and pharmacokinetic (PK) properties. All target compounds were evaluated in a hepatitis C virus (HCV) genotype 1b replicon, and the 2-oxoethyl acetate substituted compound 8t showed similar anti-HCV activity (EC50 = 0.08 nM) to that of the lead compound Daclatasvir. Moreover, the utility of prodrug 8t was demonstrated through similar exposure of the parent compound when the prodrugs were dosed in vivo. PK studies showed that prodrug 8t was an ideal candidate for a slower and sustained release form of Daclatasvir.