Substrate Analogue Renin Inhibitors Containing Replacements of Histidine in P2 or Isosteres of the Amide Bond between P3 and P2 Sites

Article abstract of DOI:10.1021/jm00115a016

Incorporation of β-alanine or γ-aminobutyric acid in position P2 of ACHPA or LeuΨVal-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 β-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.