Studies directed toward the design of orally active renin inhibitors. 2. Development of the efficacious, bioavailable renin inhibitor (2S)-2-benzyl-3- [[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (A-72517)

J Med Chem. 1993 Feb 19;36(4):460-7. doi: 10.1021/jm00056a006.

Abstract

Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a weakly basic substituent and is exemplified by compound 25. The other approach centered on the inclusion of an N-terminal sulfonamide and culminated in the discovery of inhibitor 32 (A-72517). Both 25 and 32 showed excellent bioavailability in the rat and ferret (> 25%) and, while subject to hepatic elimination in the monkey, were efficacious in this species.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Dose-Response Relationship, Drug
  • Duodenum
  • Ferrets
  • Haplorhini
  • Humans
  • Intestinal Absorption
  • Liver / metabolism
  • Molecular Structure
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Rats
  • Renin / antagonists & inhibitors*
  • Renin / blood
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology

Substances

  • Piperazines
  • Thiazoles
  • Renin
  • zankiren hydrochloride