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J Med Chem. 1991 Nov;34(11):3267-80.

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

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E. Merck Darmstadt, Preclinical Pharmaceutical Research, Germany.


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.

[Indexed for MEDLINE]

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