Janssen Research & Development, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.
J Med Chem. 2012 Nov 8;55(21):9089-106. doi: 10.1021/jm201710f. Epub 2012 Jun 8.
The design and the synthesis of several chemical subclasses of imidazole containing γ-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 γ-secretase modulatory profile by lowering Aβ42 and Aβ40 levels combined with an especially pronounced increase in Aβ38 and Aβ37 levels while leaving the total levels of amyloid peptides unchanged.
描述了几种含有γ-分泌酶调节剂（GSMs）的咪唑类化合物的设计和合成。将吡啶酮 4 构象限制为双环吡啶酮类似物，得到了具有高体外和体内活性的化合物。这导致鉴定出苯并咪唑 44a 是一种具有低纳摩尔体外效力的 GSM。在小鼠、大鼠和犬中，该化合物通过降低 Aβ42 和 Aβ40 水平，同时特别显著增加 Aβ38 和 Aβ37 水平，而不改变淀粉样肽的总水平，表现出典型的 γ-分泌酶调节特征。
