Potent, low molecular weight renin inhibitors containing a C-terminal heterocycle: hydrogen bonding at the active site.

A series of low-nanomolar renin inhibitors containing novel C-terminal heterocycles has been designed by formally cyclizing the C-terminus of a glycol-based inhibitor to the second hydroxyl. Molecular modeling suggests that the heterocyclic oxygen hydrogen bonds as an acceptor to the flap region of renin and that the second hydroxyl in the glycol-based inhibitors behaves similarly.

Renin inhibitors based on dipeptide analogues. Incorporation of the hydroxyethylene isostere at the P2/P3 sites.

The synthesis of a series of renin inhibitors in which the P2 and P3 amino acids are replaced with the hydroxyethylene dipeptide isostere is reported. In vitro evaluation of the inhibitors has revealed that this isostere is an acceptable amide-bond replacement in which activity is maintained and stability is enhanced. Structure-activity relationships of this series resemble but do not parallel those of the corresponding dipeptide-containing inhibitors.

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.