2-AMINO-4H-3,1-BENZOXAZIN-4-ONES AS INHIBITORS OF C1R SERINE-PROTEASE

A series of 2-amino-4H-3,1-benzoxazin-4-ones have been synthesized and evaluated as inhibitors of the complement enzyme C1r. C1r is a serine protease at the beginning of the complement cascade, and complement a ctivation by beta-amyloid may represent a major contributing pathway t o the neuropathology of Alzheimer's disease. Compounds such as ro-2-[( 2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (32) and 7-methyl-2-[(2-io dophenyl)amino]benz[d] 4-one (37) show improved potency compared to th e reference compound FUT-175. Many of these active compounds also poss ess increased selectivity for C1r compared to trypsin and enhanced hyd rolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4-one (1).