title: Synthesis and optimization of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one based inhibitors of human neutrophil elastase.
abstract: The hit-to-lead optimization of the HNE inhibitor 5-methyl-2-(2-phenoxy-pyridin-3-yl)-benzo[d][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-benzo[d][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.
authors: ActivX Biosciences, Inc, La Jolla, CA 92037, USA. kevins@activx.com
authors: Kevin R
authors: KR
authors: Shreder
authors: Julia
authors: J
authors: Cajica
authors: Lingling
authors: L
authors: Du
authors: Allister
authors: A
authors: Fraser
authors: Yi
authors: Y
authors: Hu
authors: Yasushi
authors: Y
authors: Kohno
authors: Emme C K
authors: EC
authors: Lin
authors: Steve J
authors: SJ
authors: Liu
authors: Eric
authors: E
authors: Okerberg
authors: Lan
authors: L
authors: Pham
authors: Jiangyue
authors: J
authors: Wu
authors: John W
authors: JW
authors: Kozarich
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D048588:Benzoxazines; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase