Synthesis and optimization of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one based inhibitors of human neutrophil elastase |
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| Authors: | Kevin R Shreder Julia Cajica Lingling Du Allister Fraser Yi Hu Yasushi Kohno Emme CK Lin Steve J Liu Eric Okerberg Lan Pham Jiangyue Wu John W Kozarich |
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| Institution: | 1. ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA;2. Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd, 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan |
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| Abstract: | The hit-to-lead optimization of the HNE inhibitor 5-methyl-2-(2-phenoxy-pyridin-3-yl)-benzod]1,3]oxazin-4-one is described. A structure–activity relationship study that focused on the 5 and 7 benzoxazinone positions yielded the optimized 5-ethyl-7-methoxy-benzod]1,3]oxazin-4-one core structure. 2-2-(4-Methyl-piperazin-1-yl)-pyridin-3-yl] derivatives of this core were shown to yield HNE inhibitors of similar potency with significantly different stabilities in rat plasma. |
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