Inhibition of serine proteases: activity of 1,3-diazetidine-2,4-diones

• Published in: Bioorganic & medicinal chemistry letters 2001-07, Vol.11 (13), p.1691-1694
• Main Authors: Aoyama, Yasunori, Uenaka, Masaaki, Konoike, Toshiro, Hayasaki-Kajiwara, Yoko, Naya, Noriyuki, Nakajima, Masatoshi
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Azetidines - chemistry; Azetidines - pharmacology; Biological and medical sciences; Cathepsin G; Cathepsins - antagonists & inhibitors; Chymotrypsin - antagonists & inhibitors; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases; Leukocyte Elastase - antagonists & inhibitors; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Serine Endopeptidases; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Substrate Specificity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00264-5

The present work demonstrates that the 1,3-diazetidine-2,4-dione nucleus is effective as a scaffold of serine protease inhibitors. Compound 1 displayed high activity against human cathepsin G and α-chymotrypsin (0.39, 0.69 nM). Compound 6 exhibited 0.85 nM inhibition of human chymase. Compound 10 was a selective inhibitor against human neutrophil elastase. We discovered a new class of serine protease inhibitors, 1,3-diazetidine-2,4-dione derivatives. The present work demonstrates that the 1,3-diazetidine-2,4-dione nucleus is effective as a scaffold of serine protease inhibitors.