7-烷基醚类illudalic acid类似物的合成及LAR抑制活性研究(英文)  

Synthesis and LAR inhibition of 7-alkoxy analogues of illudalic acid

作　　者：凌青[1] 周越洋[2] 蔡正良[1] 张亚徽 熊兵[1] 马兰萍[1] 王昕[1] 李欣[1] 李佳[2] 沈竞康[1] 

机构地区：[1]中国科学院上海药物研究所新药研究国家重点实验室,上海201203 [2]国家新药筛选中心,上海201203

出　　处：《药学学报》2010年第11期1385-1397,共13页Acta Pharmaceutica Sinica

基　　金：supported by the Hi-tech Research and Development Program of China through Grant No.2006AA02Z315(L.-P.M)and No.2007AA09Z402(J.L);National Science & Technology Major Project"Key New Drug Creation and Manufacturing Program"of China(No.2009ZX09501-010 and No.2009ZX09301-001).

摘　　要：为了获得更强的活性和更好的选择性,基于构效关系合成了一系列7-烷基醚类illudalic acid类似物。这些化合物对人源白细胞共同抗原相关蛋白(LAR)显示亚微摩尔的抑制活性,其中15e的IC50达到180 nmol.L?1。它们是迄今发现的最强效的LAR小分子抑制剂。这些类似物除了对高度同源的PTPσ外,对蛋白酪氨酸磷酸酯酶(PTPs)家族的其他成员均显示出良好的选择性,其中化合物15f对LAR的选择性是对PTP1B抑制活性的120倍。这些强效选择性抑制剂的发现具有重要意义,既可以作为LAR的研究工具同时可能成为II型糖尿病的治疗剂。To obtain higher potency and specificity,a series of 7-alkoxy analogues of illudalic acid was synthesized on the base of structure-activity relationship（SAR）.All of these compounds exhibited submicromolar inhibition of the enzyme when tested against human leukocyte common antigen-related phosphatase（LAR）（for example,for 15e,IC50 = 180 nmol.L？1）.They represent the most potent small-molecule inhibitors of LAR so far.These analogues also display excellent selectivity for LAR over other protein tyrosine phosphatases（PTPs） except for the highly homologous PTPσ.The compound 15f is of 120-fold selectivity for LAR versus PTP-1B inhibition.The development of potent enzyme-specific inhibitors is so important that they may serve both as tools to study the role of LAR and as therapeutic agents for treatment of type II diabetes.

关 键 词：人源白细胞共同抗原相关蛋白 illudalic酸 抑制剂 类似物 构效关系 

分 类 号：R916[医药卫生—药学]