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Renin inhibitors. Design and synthesis of a new class of conformationally restricted analogues of angiotensinogen.

Abstract：

:Molecular modeling methods have been used to design a novel series of conformationally constrained cyclic peptide inhibitors of human renin. Three goals were defined: enhanced inhibitory potency, high specificity for renin, and increased metabolic stability. Three cyclic compounds were synthesized with ring sizes 10, 12, and 14, based upon a linear hexapeptide inhibitor with a reduced amide replacing the scissile bond at the active site. When tested, the 14-membered-ring compound was as potent an inhibitor of human renin as the parent while the 12-membered-ring compound was 6-fold more potent than the parent against mouse renin. However, the 10-membered-ring compound was inactive against both renins. The lack of potency of the 10-membered compound was explained by using NMR and molecular modeling techniques. It forms another conformation in solution that is inconsistent with binding at the active site. The cyclic compounds did not inhibit either pepsin or cathepsin D significantly. The cyclic modification rendered these inhibitors significantly resistant to cleavage by chymotrypsin and thus prevented loss of activity by this enzyme. Thus, the goals of enhanced inhibitory potency, high specificity, and metabolic stability were achieved in the series of compounds.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Sham HL,Bolis G,Stein HH,Fesik SW,Marcotte PA,Plattner JJ,Rempel CA,Greer J

doi

10.1021/jm00397a003

subject

Has Abstract

pub_date

1988-02-01 00:00:00

pages

284-95

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

31

pub_type

杂志文章

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