257610-91-6Relevant academic research and scientific papers
2-(Diethylamino)thieno[1,3]oxazin-4-ones as stable inhibitors of human leukocyte elastase
Gütschow, Michael,Kuerschner, Lars,Neumann, Ulf,Pietsch, Markus,L?ser, Reik,Koglin, Norman,Eger, Kurt
, p. 5437 - 5447 (1999)
A series of 2-(diethylamino)thieno[1,3]oxazin-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 thieno[2,3-d][1,3]oxazin-4-ones bearing various substituents at positions 5 and 6. Both thieno[2,3-d] and thieno[3,2-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- [1]benzothieno[2,3-d][1,3]oxazin-4-one, exhibited a K(i) value of 5.8 nM. 2-(Diethylamino)thieno[1,3]oxazin-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.
