SUBSTRATE-ANALOG RENIN INHIBITORS CONTAINING REPLACEMENTS OF HISTIDINE IN P2 OR ISOSTERES OF THE AMIDE BOND BETWEEN P3 AND P2 SITES

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.