title: Inhibition of human chymase by 2-amino-3,1-benzoxazin-4-ones.
abstract: A series of 2-sec.amino-4H-3,1-benzoxazin-4-ones was evaluated as acyl-enzyme inhibitors of human recombinant chymase. The compounds were also assayed for inhibition of human cathepsin G, bovine chymotrypsin, and human leukocyte elastase. Introduction of an aromatic moiety into the 2-substituent resulted in strong inhibition of chymase, cathepsin G, and chymotrypsin. Extension of the N(Me)CH2Ph substituent by one methylene unit was unfavourable to inhibit these proteases. Towards chymase, 2-(N-benzyl-N-methylamino)-4H-3,1-benzoxazin-4-one (32) and 2-(N-benzyl-N-methylamino)-6-methyl-4H-3,1-benzoxazin-4-one (33) were found to exhibit Ki values of 11 and 17 nM, respectively, and form stable acyl-enzymes with half-lives of 53 and 25 min, respectively. Benzoxazinone 33 also inhibited the human chymase-catalyzed formation of angiotensin 11 from angiotensin I.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Neumann
authors.forename: N M
authors.initials: NM
authors.lastname: Schechter
authors.forename: M
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D000465:Algorithms; D000803:Angiotensin I / Q000378:metabolism; D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002417:Cattle; D053818:Chymases; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D010078:Oxazines; D011480:Protease Inhibitors; D014361:Trypsin Inhibitors; D000803:Angiotensin I; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053818:Chymases