Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme
Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme
复制标题
DOI：
10.1016/j.bmcl.2016.07.011
复制
发表时间：
2016-08-15
影响因子：
2.7
通讯作者：
Wagner, Steven L.
中科院分区：
文献类型：
--
作者：
Rynearson, Kevin D.;Buckle, Ronald N.;Wagner, Steven L.
描述了一系列新型氨基噻唑衍生的γ-分泌酶调节剂的设计和构建。对先导化合物 1 的末端苯基 D 环进行杂环取代的掺入是为了使效力与有利的药物样特性相一致。 γ-分泌酶调节剂 28 对 A beta 42 的体外抑制表现出良好的活性，并且 ADME 和理化性质（包括水溶性）有显着改善。化合物 28 在小鼠体内的药代动力学评估显示出良好的脑渗透性，以及良好的清除率、半衰期和分布体积，这些共同支持了此类化合物的持续开发。 (C) 2016 年由爱思唯尔有限公司出版。
The design and construction of a series of novel aminothiazole-derived gamma-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. gamma-Secretase modulator 28 displayed good activity for in vitro inhibition of A beta 42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds. (C) 2016 Published by Elsevier Ltd.