C-terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties

J Med Chem. 1992 May 15;35(10):1735-46. doi: 10.1021/jm00088a007.


We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Dipeptides / pharmacology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Ferrets
  • Hemodynamics / drug effects
  • Humans
  • Macaca fascicularis
  • Male
  • Renin / antagonists & inhibitors*
  • Renin / blood
  • Renin / metabolism


  • Dipeptides
  • Enzyme Inhibitors
  • enalkiren
  • Renin