化学
羧酸盐
噻吩
效力
羧酸
四唑
立体化学
组合化学
小分子
酶
化学合成
药物发现
有机化学
生物化学
体外
作者
Zhengming Wan,Bruce Follows,Steve Kirincich,Douglas P. Wilson,Eva Binnun,Weixin Xu,Diane Joseph‐McCarthy,Junjun Wu,Michael J. Smith,Yanling Zhang,May Tam,David V. Erbe,Steve Tam,Eddine Saiah,Jinbo Lee
标识
DOI:10.1016/j.bmcl.2007.02.043
摘要
The following account describes our systematic effort to replace one of the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active hits were validated using enzymatic assays before pursuing efforts to improve the potency. Only when the C2 carboxylic acid was replaced with another ionizable functional group was reversible and competitive inhibition retained. Use of a tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to the discovery of two unique starting series that showed improved permeability (PAMPA) and potency of the order of 300 nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.
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