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.