Journal of Medicinal Chemistry p. 1978 - 1983 (1987)
Update date:2022-08-05
Topics: Experimental terms Renin inhibitors Incorporation Dipeptide Analogues Dehydrohydroxyethylene Isostere Scissile Bond
Kempf, Dale J.
Lara, Ed de
Stein, Herman H.
Cohen, Jerome
Plattner, Jacob J.
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.
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