Renin inhibitors based on novel dipeptide analogs. Incorporation of the dehydrohydroxyethylene isostere at the scissile bond
- 1 November 1987
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 30 (11) , 1978-1983
- https://doi.org/10.1021/jm00394a008
Abstract
The design and synthesis of renin inhibitors that incorporate the novel dipeptide isostere (4S,5S)-5-amino-6-cyclohexyl-4-hydroxyhex-1-ene-2-carboxylic acid as a transition-state analogue are described. Titanium-promoted condensation of dilithiated N-alkylmethacrylamides with protected amino aldehydes results in efficient preparation of protected dipeptide analogues 7 and 8. Incorporation of 7 into the partial sequence of angiotensinogen affords potent in vitro inhibitors of human renin. Further chemical manipulation of the unsaturated amide moiety allows the study of structure-activity relationships in both the P1'' and P2'' sites. Details of the syntheses, stereochemical determinations, and in vitro renin inhibition are presented.This publication has 5 references indexed in Scilit:
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