Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Bioorg Med Chem Lett. 2010 Apr 1;20(7):2279-82. doi: 10.1016/j.bmcl.2010.02.008. Epub 2010 Feb 6.
The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.
本文披露了一类新型嘌呤类 γ-分泌酶调节剂的开发，它们有可能用于治疗阿尔茨海默病。对先前披露的嘧啶类化合物进行优化，得到了一系列有效的嘌呤类 γ-分泌酶调节剂，其对 Notch 切割的抑制活性具有 300 至 2000 倍的体外选择性，并且在 APP-YAC 转基因小鼠模型中选择性地降低 Alphabeta42。
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