Hagishita S, Yamada M, Shirahase K, Okada T, Murakami Y, Ito Y, Matsuura T, Wada M, Kato T, Ueno M, Chikazawa Y, Yamada K, Ono T, Teshirogi I, Ohtani M
Shiongi Research Laboratories, Shionogi & Co., Ltd, Osaka, Japan.
J Med Chem. 1996 Sep 13;39(19):3636-58. doi: 10.1021/jm960395q.
Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.
磷脂酶A2是一种水解某些细胞磷脂sn-2位的酶。释放出的溶血磷脂和花生四烯酸是各种生物活性产物生物合成的前体。由于人类非胰腺分泌型磷脂酶A2在几种病理状态患者的血液中含量很高，强效的分泌型磷脂酶A2抑制剂已被认为是有用的药物。在此我们描述中氮茚和茚衍生物的合成、构效关系及抑制活性。1-（氨甲酰基甲基）中氮茚衍生物和1-草氨酰中氮茚衍生物表现出非常强的抑制活性。前者对空气氧化不稳定，但后者在稳定性和效力方面均有改善。一些化合物接近显色测定的化学计量极限。
