Design and synthesis of imidazole N–H substituted amide prodrugs as inhibitors of hepatitis C virus replication. Issue 16 (15th August 2015)

• Record Type: Journal Article
• Authors: Zong, Xi; Cai, Jin; Chen, Junqing; Wang, Peng; Zhou, Gaoxin; Chen, Bo; Li, Wei; Ji, Min
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 16(2015)
• Page Start: 3147
• Page End: 3150
• Publication Date: 2015-08-15
• Subjects: Hepatitis C virus -- NS5A -- Prodrug -- Daclatasvir -- Pharmacokinetics; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.06.006
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: A design for DCV prodrugs. Abstract: Twenty-five novel imidazole N–H substitutedDaclatasvir (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 compound8t showed similar anti-HCV activity (EC50 = 0.08 nM) to that of the lead compoundDaclatasvir . Moreover, the utility of prodrug8t was demonstrated through similar exposure of the parent compound when the prodrugs were dosed in vivo. PK studies showed that prodrug8t was an ideal candidate for a slower and sustained release form ofDaclatasvir .