Dipeptide glycols: a new class of renin inhibitors.
The discovery of a new class of novel renin inhibitors consisting of protected dipeptide amides derived from aminoglycols (Formula I) prompted a study of structure-activity in vitro and efficacy in vivo. Thus, Boc-L-Phe-N-[(1S,2R)-1-benzyl-(2,3-dihydroxy)propyl]-L-leucinamide (1) and the corresponding histidinamide (2) inhibit human renin in vitro (IC50: 8.7 X 10-6 M and 2.6 X 10-6 M, respectively). Compound 1 has a slight inhibitory effect on pepsin and compound 2 does not inhibit pepsin at all (at 10-4M); these compounds are inactive against rat renin. Compound 1 is efficacious in lowering plasma renin activity in the Rhesus monkey (i.v.). Results indicate that this new class of low molecular weight inhibitors is specific for human renin and thus constitutes a new source of drug candidates.
D000818:Animals; D004151:Dipeptides / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology; D006018:Glycols / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D010434:Pepsin A / Q000037:antagonists & inhibitors; D010436:Pepstatins / Q000494:pharmacology; D051381:Rats; D013552:Swine; D000092502:Renin Inhibitors
D004151:Dipeptides; D005665:Furosemide; D006018:Glycols; D010434:Pepsin A; D010436:Pepstatins; D000092502:Renin Inhibitors; C014195:Streptomyces pepsin inhibitor; C031375:pepstatin