title: Novel thieno[2,3-d][1,3]oxazin-4-ones as inhibitors of human leukocyte elastase.
abstract: A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with Ki values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.
authors.affiliation: Institute of Pharmacy, University of Leipzig, D-04103 Leipzig, Germany, and Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Gütschow
authors.forename: U
authors.initials: U
authors.lastname: Neumann
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010078:Oxazines; D013876:Thiophenes; D019272:Leukocyte Elastase