Renin inhibitors. Design and synthesis of a new class of conformationally restricted analogues of angiotensinogen.
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.
Sham
H L
HL
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Bolis
G
G
Stein
H H
HH
Fesik
S W
SW
Marcotte
P A
PA
Plattner
J J
JJ
Rempel
C A
CA
Greer
J
J
D000808:Angiotensinogen / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002918:Chymotrypsin / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000808:Angiotensinogen; D002918:Chymotrypsin; D000092502:Renin Inhibitors