beta-Lactam derivatives as enzyme inhibitors: N-substituted derivatives of (S)-4-oxoazetidine-2-carboxylate as inhibitors of elastase and papain.
N-Alkyl and N-acyl substituted 4-oxoazetidine-2-carboxylates are synthesized and evaluated as inhibitors of the proteases porcine pancreatic elastase (PPE) and papain. The compounds are obtained by alkylation or acylation at the nitrogen of benzyl (S)-4-oxoazetidine-2-carboxylate, which is synthesized by a modified literature procedure. The enzymatic assays prove some derivatives to be effective inhibitors of PPE and/or papain. The N-BOC protected amino acid derivatives 10 and 13 inhibit PPE reversibly with KI-values in the micromolar range. On the other hand, papain is inactivated irreversibly by benzyl (S)-2-(benzyloxycarbonyl)azetidin-1-acetate (6).
Achilles
K
K
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Ernst-Moritz-Arndt-Universität Greifswald, Germany.
Schneider
M
M
Schirmeister
T
T
Otto
H H
HH
D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D010206:Papain / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013552:Swine; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000494:pharmacology
D001384:Azetidines; D011480:Protease Inhibitors; D047090:beta-Lactams; D010196:Pancreatic Elastase; D010206:Papain