Novel substituted pyrimidines as HCV replication (replicase) inhibitors.

Academic Article

Abstract

  • Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase).
  • Keywords

  • Animals, Dose-Response Relationship, Drug, Hepacivirus, Hepatitis C, Microbial Sensitivity Tests, Molecular Structure, Pyrimidines, Rats, Stereoisomerism, Structure-Activity Relationship, Virus Replication
  • Digital Object Identifier (doi)

    Authorlist

  • Kwong CD; Clark JL; Fowler AT; Geng F; Kezar HS; Roychowdhury A; Reynolds RC; Maddry JA; Ananthan S; Secrist JA
  • Start Page

  • 1160
  • End Page

  • 1164
  • Volume

  • 22
  • Issue

  • 2