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.
Kempf
D J
DJ
Cardiovascular Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
de Lara
E
E
Stein
H H
HH
Cohen
J
J
Plattner
J J
JJ
D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D004151:Dipeptides; D000092502:Renin Inhibitors