Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators
Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators
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DOI：
10.1021/jm201710f
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发表时间：
2012-11-08
影响因子：
7.3
通讯作者：
Gijsen, Harrie J. M.
中科院分区：
文献类型：
--
作者：
Bischoff, Francois;Berthelot, Didier;Gijsen, Harrie J. M.
设计和合成了几种含咪唑的γ-分泌酶调节剂（GSMs）。将吡啶酮4构象限制为双环吡啶酮电子等排体已导致化合物具有高的体外和体内效力。这导致苯并咪唑44 a在体外被鉴定为具有低纳摩尔效力的GSM。在小鼠、大鼠和犬中，该化合物通过降低A β 42和A β 40水平以及A β 38和A β 37水平的特别显著增加而显示出典型的γ-分泌酶调节特征，同时保持淀粉样肽的总水平不变。
The design and the synthesis of several chemical subclasses of imidazole containing gamma-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted, in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical gamma-secretase modulatory profile by lowering A beta 42 and A beta 40 levels combined with an especially pronounced increase in A beta 38 and A beta 37 levels while leaving the total levels of amyloid peptides unchanged.