5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

Academic Article

Abstract

  • Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol. © 2012 Elsevier Ltd. All rights reserved.
  • Digital Object Identifier (doi)

    Author List

  • Arasappan A; Bennett F; Girijavallabhan V; Huang Y; Huelgas R; Alvarez C; Chen L; Gavalas S; Kim SH; Kosinski A
  • Start Page

  • 3229
  • End Page

  • 3234
  • Volume

  • 22
  • Issue

  • 9