title: Design and synthesis of imidazole N-H substituted amide prodrugs as inhibitors of hepatitis C virus replication.
abstract: 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.
authors.affiliation: School of Chemistry & Chemical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zong
authors.affiliation: School of Chemistry & Chemical Engineering, Southeast University, Nanjing 210096, China. Electronic address: caijin@seu.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Cai
authors.affiliation: School of Chemistry & Chemical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Gaoxin
authors.initials: G
authors.lastname: Zhou
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China; Suzhou Key Laboratory of Biomaterials and Technologies & Collaborative Innovation Center of Suzhou Nano Science and Technology, Suzhou 215123, China. Electronic address: jimin@seu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002219:Carbamates; D015195:Drug Design; D006207:Half-Life; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D009584:Nitrogen / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011759:Pyrrolidines; D051381:Rats; D014633:Valine / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000577:Amides; D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011355:Prodrugs; D011759:Pyrrolidines; C029899:imidazole; D006859:Hydrogen; D014633:Valine; C549273:daclatasvir; D009584:Nitrogen
keywords: Daclatasvir; Hepatitis C virus; NS5A; Pharmacokinetics; Prodrug