Design and synthesis of potent, selective, and orally active fluorine-containing renin inhibitors

J Med Chem. 1992 Jan;35(1):2-14. doi: 10.1021/jm00079a001.


A series of primate renin inhibitors containing difluorocarbinol and difluoroketone groups at the P1-P1' position have been synthesized and studied both in vitro and in vivo. In vitro, the compounds were evaluated as inhibitors of monkey renin and the closely related aspartic proteinase, cathepsin D (bovine), as a measure of enzyme selectivity. Interestingly, the difluoroketone derivatives showed greatly reduced selectivity compared with the corresponding alcohols. However, selectivity could be enhanced by judicious choice of other substituents. Sites influencing selectivity, included not only P2, which is well-known to strongly affect selectivity, but also the P4, P1-P1', and P2' sites. These results make possible the design of inhibitors with a greater selectivity for either renin versus cathepsin D. In vivo several of the compounds in the difluoroketone series have shown good oral activity in the salt depleted normotensive cynomolgus monkey model.

MeSH terms

  • Administration, Oral
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Cathepsin B / antagonists & inhibitors
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Hydrocarbons, Fluorinated / administration & dosage
  • Hydrocarbons, Fluorinated / chemical synthesis*
  • Hydrocarbons, Fluorinated / pharmacology
  • Macaca fascicularis
  • Male
  • Renin / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Hydrocarbons, Fluorinated
  • Cathepsin B
  • Aspartic Acid Endopeptidases
  • Renin