ABSTRACT
3-Benzylazetidine-2-one derivatives were designed and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 3-benzylazetidine-2-ones led to compounds 23, which exhibited 3.1 nM inhibition of human chymase and enhancement of stability in human plasma (t(1/2) 6h).
Subject(s)
Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Serine Endopeptidases/drug effects , Azetidines/pharmacology , Blood/metabolism , Chymases , Drug Design , Humans , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
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 alpha-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.
Subject(s)
Azetidines/pharmacology , Cathepsins/antagonists & inhibitors , Chymotrypsin/antagonists & inhibitors , Serine Proteinase Inhibitors/pharmacology , Azetidines/chemistry , Cathepsin G , Humans , Leukocyte Elastase/antagonists & inhibitors , Serine Endopeptidases , Serine Proteinase Inhibitors/chemistry , Substrate SpecificityABSTRACT
1-Oxacephem derivatives were synthesized and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 1-oxacephems led to compound 34, which exhibited 6 nM inhibition of human chymase and high selectivity for human chymase compared to other serine enzymes.
Subject(s)
Cephalosporins/chemical synthesis , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Cephalosporins/chemistry , Cephalosporins/pharmacology , Chymases , Drug Design , Humans , Molecular Structure , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
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).