title: 2-(diethylamino)thieno1,3ŏxazin-4-ones as stable inhibitors of human leukocyte elastase.
abstract: A series of 2-(diethylamino)thieno1,3ŏxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase (HLE). The Gewald thiophene synthesis was utilized to obtain several ethyl 2-aminothiophene-3-carboxylates. These precursors were subjected to a five-step route to obtain thieno2,3-d1,3ŏxazin-4-ones bearing various substituents at positions 5 and 6. Both thieno2,3-d and thieno3,2-d fused oxazin-4-ones possess extraordinary chemical stability, which was expressed as rate constants of the alkaline hydrolysis. The kinetic parameters of the HLE inhibition were determined. The most potent compound, 2-(diethylamino)-4H-1benzothieno2,3-d1,3ŏxazin-4-one, exhibited a K(i) value of 5.8 nM. 2-(Diethylamino)thieno1, 3ŏxazin-4-ones act as acyl-enzyme inhibitors of HLE, similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. The isosteric benzene-thiophene replacement accounts for an enhanced stability of the acyl-enzyme intermediates.
authors.affiliation: Institute of Pharmacy, University of Leipzig, D-04103 Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gütschow
authors.forename: L
authors.initials: L
authors.lastname: Kuerschner
authors.forename: U
authors.initials: U
authors.lastname: Neumann
authors.forename: M
authors.initials: M
authors.lastname: Pietsch
authors.forename: R
authors.initials: R
authors.lastname: Löser
authors.forename: N
authors.initials: N
authors.lastname: Koglin
authors.forename: K
authors.initials: K
authors.lastname: Eger
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
chemical_list: D004791:Enzyme Inhibitors; D010078:Oxazines; D019272:Leukocyte Elastase