Hays S J, Caprathe B W, Gilmore J L, Amin N, Emmerling M R, Michael W, Nadimpalli R, Nath R, Raser K J, Stafford D, Watson D, Wang K, Jaen J C
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J Med Chem. 1998 Mar 26;41(7):1060-7. doi: 10.1021/jm970394d.
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 activation by beta-amyloid may represent a major contributing pathway to the neuropathology of Alzheimer's disease. Compounds such as 7-chloro-2-[(2-iodophenyl)-amino]benz[d][1,3]oxazin-4-one (32) and 7-methyl-2-[(2-iodophenyl)amino]benz[d][1,3]oxazin-4-one (37) show improved potency compared to the reference compound FUT-175. Many of these active compounds also possess increased selectivity for C1r compared to trypsin and enhanced hydrolytic stability relative to 2-(2-iodophenyl)-4H-3,1-benzoxazin-4-one (1).
已经合成了一系列2-氨基-4H-3,1-苯并恶嗪-4-酮，并将其作为补体酶C1r的抑制剂进行了评估。C1r是补体级联反应起始处的一种丝氨酸蛋白酶，β-淀粉样蛋白激活补体可能是阿尔茨海默病神经病理学的主要促成途径。与参考化合物FUT-175相比，7-氯-2-[(2-碘苯基)氨基]苯并[d][1,3]恶嗪-4-酮（32）和7-甲基-2-[(2-碘苯基)氨基]苯并[d][1,3]恶嗪-4-酮（37）等化合物显示出更高的效力。与胰蛋白酶相比，这些活性化合物中的许多对C1r也具有更高的选择性，并且相对于2-(2-碘苯基)-4H-3,1-苯并恶嗪-4-酮（1）具有更高的水解稳定性。
