title: A novel synthetic inhibitor of endopeptidase-24.15.
abstract: A novel synthetic inhibitor of endopeptidase-24.15 (EP-24.15, EC 3.4.24.15), N-[(2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidine carbonyl] -L-phenylalanine (SA898) is described. This compound inhibited rat EP-24.15 competitively with an IC50 of 23 nM and Ki of 9.1 nM. These values were, respectively, 9.6 times and 6.3 times smaller than those for N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanyl-p-aminobenzoate (cFP-AAF-pAB), which was one of the most potent inhibitors thus far reported. The inhibitory effect of SA898 on other endopeptidases, angiotensin converting enzyme (ACE, EC 3.4.15.1) and endopeptidase-24.11 (EP-24.11, EC 3.4.24.11) was also studied. SA898 inhibited ACE significantly, but the potency was about 20-fold lower than that for EP-24.15 in terms of the Ki value. The inhibitory effect of SA898 on EP-24.11 was almost negligible (Ki = 28 microM). In addition, the inhibitory activities of several SA898-related compounds were examined. Based on these data, the structure-activity relationships for EP-24.15 inhibitors are discussed.
authors.affiliation: Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ukai
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Mita
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; C107155:SA 898; D013844:Thiazoles; D053778:Thiazolidines; C064939:N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanine-4-aminobenzoate; D010649:Phenylalanine; D008666:Metalloendopeptidases; D015260:Neprilysin; C022510:thimet oligopeptidase