Renin inhibitors based on novel dipeptide analogues. Incorporation of the dehydrohydroxyethylene isostere at the scissile bond.

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.