1-Oxacephem-based human chymase inhibitors: discovery of stable inhibitors in human plasma

• Published in: Bioorganic & medicinal chemistry letters Vol. 10; no. 21; pp. 2403 - 2406
• Main Authors: Aoyama, Yasunori, Uenaka, Masaaki, Konoike, Toshiro, Iso, Yasuyoshi, Nishitani, Yasuhiro, Kanda, Akiko, Naya, Noriyuki, Nakajima, Masatoshi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06-11-2000; Elsevier
• Subjects: Biological and medical sciences; Cardiovascular system; Cephalosporins - blood; Cephalosporins - chemical synthesis; Cephalosporins - chemistry; Cephalosporins - pharmacology; Chymases; Enzyme Stability; Humans; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Plasma - chemistry; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - blood; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Human; Tetrazole derivatives; Serine endopeptidases; Enzyme; Lactam; Enzyme inhibitor; Selectivity; In vitro; Chymase; Peptidases; Hydrolysis resistance; Cephalosporin derivatives; Structure activity relation; Carboxylic acid; Bicyclic compound; Hydrolases; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)00489-3

1-Oxacephem derivatives were evaluated as a novel series of chymase inhibitors. The structure–activity relationship studies of 1-oxacephems led to compounds
15, which exhibited 27
nM inhibition of human chymase and improvement of stability in human plasma (
t
1/2 1.5
h).