2. Academic Validation
  3. Design and synthesis of imidazole N-H substituted amide prodrugs as inhibitors of hepatitis C virus replication

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

  • Bioorg Med Chem Lett. 2015 Aug 15;25(16):3147-50. doi: 10.1016/j.bmcl.2015.06.006.
Xi Zong 1,  Jin Cai 2,  Junqing Chen 1,  Peng Wang 3,  Gaoxin Zhou 3,  Bo Chen 3,  Wei Li 4,  Min Ji 5
Affiliations

Affiliations

  • 1 School of Chemistry & Chemical Engineering, Southeast University, Nanjing 210096, China.
  • 2 School of Chemistry & Chemical Engineering, Southeast University, Nanjing 210096, China. Electronic address: [email protected].
  • 3 School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China.
  • 4 Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
  • 5 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: [email protected].
PMID: 26077493 DOI: 10.1016/j.bmcl.2015.06.006
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.

Keywords

Daclatasvir; Hepatitis C virus; NS5A; Pharmacokinetics; Prodrug.

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