title: Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo.
abstract: A structure-activity analysis of peptides containing backbone C alpha-methyl and N alpha-methyl modifications led to the discovery of potent renin inhibitors with high metabolic stability. In vitro, Boc-Pro-Phe-N alpha-MeHis-Leu psi-[CHOHCH2]Val-Ile-Amp (XII) is a potent inhibitor of human plasma renin with IC50 of 0.26 nM. It is a much weaker inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (IC50 = 6 microM). It was shown not to be degraded by a rat liver homogenate preparation. In vivo, it inhibited plasma renin activity and lowered blood pressure of furosemide-treated cynomolgus monkeys. At a dose of 5 mg/kg iv, the pronounced hypotensive response persisted for greater than 3 h postinfusion.
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013997:Time Factors; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D009842:Oligopeptides; D010455:Peptides; D011480:Protease Inhibitors; D000092502:Renin Inhibitors; C050898:ditekiren