Synthesis and optimization of 2-pyridin-3-yl-benzo[d][1,3]oxazin-4-one based inhibitors of human neutrophil elastase.
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.
Shreder
Kevin R
KR
ActivX Biosciences, Inc, La Jolla, CA 92037, USA. kevins@activx.com
Cajica
Julia
J
Du
Lingling
L
Fraser
Allister
A
Hu
Yi
Y
Kohno
Yasushi
Y
Lin
Emme C K
EC
Liu
Steve J
SJ
Okerberg
Eric
E
Pham
Lan
L
Wu
Jiangyue
J
Kozarich
John W
JW
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
D048588:Benzoxazines; D015842:Serine Proteinase Inhibitors; D019272:Leukocyte Elastase