Key result
Angiotensinogen analogues containing a novel dipeptide isostere were synthesized and shown to be potent inhibitors of human plasma renin.
Novel angiotensinogen analogues containing a dihydroxyethylene isostere act as transition-state analogues and potently inhibit human plasma renin in vitro.
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May aid renin inhibitor development; leaves open clinical translation in hypertension.
A highly stereoselective synthesis of 2(R)-[5(R)-[1(S)-[(tert-butyloxycarbonyl)amino]-3-methylbutyl]-2,2- dimethyl-4(R)-dioxolanyl]-3-methylbutanoic acid is described. This is a suitably protected carboxylic acid useful as an intermediate for the preparation of renin inhibitory peptides. Angiotensinogen analogues such as peptides IX and X that contain the dipeptide isostere (2R,3R,4R,5S)-5-amino-3,4-dihydroxy-2-isopropyl-7-methyloctanoic acid residue at the scissile site are shown to be potent inhibitors of human plasma renin. The glycol moiety in this novel acid, dihydroxyethylene isostere, is suggested to act as a transition-state analogue and mimics the tetrahedral intermediate formed during the enzyme-catalyzed hydrolysis of the peptidic bond.
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Thaisrivongs et al. (1987) studied this question. Angiotensinogen analogues (peptides IX and X) was evaluated on Inhibition of human plasma renin. Angiotensinogen analogues containing a novel dipeptide isostere were synthesized and shown to be potent inhibitors of human plasma renin.
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