Substrate analogue renin inhibitors containing replacements of histidine in P2 or isosteres of the amide bond between P3 and P2 sites

J Med Chem. 1991 Nov;34(11):3267-80. doi: 10.1021/jm00115a016.


Incorporation of beta-alanine or gamma-aminobutyric acid in position P2 of ACHPA or Leu psi [CHOHCH2]Val-based tetrapeptides gave highly active renin inhibitors (compounds V, VI, and XVII) with high specificity for renin and a remarkable stability against chymotrypsin. Replacement of the amide bond between P2 and P3 by isosteres (ketomethylenes, hydroxyethylenes, and the corresponding thio-insertion analogues) led to compounds (VIII-XIII, XVIII, and XIX) with renin inhibitory activity in the nanomolar range. Oral activity was achieved by incorporation of polar functionalities at the N-terminus of beta-alanine-containing tetrapeptides. One of these compounds (XXVIII) was chosen for further studies. This inhibitor demonstrated excellent efficacy and a long duration of action after intravenous and oral administration to cynomolgus monkeys.

MeSH terms

  • Administration, Oral
  • Amides / chemical synthesis*
  • Amides / pharmacology
  • Animals
  • Blood Pressure / drug effects
  • Chromatography, High Pressure Liquid
  • Female
  • Histidine*
  • Humans
  • Macaca fascicularis
  • Renin / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Amides
  • Histidine
  • Renin