Department of Medicinal Chemistry, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2011 Dec 15;21(24):7277-80. doi: 10.1016/j.bmcl.2011.10.047. Epub 2011 Oct 19.
Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats.
从非甾体抗炎药（NSAIDs）-型γ-分泌酶调节剂（GSMs）的文献实例出发，我们采用支架设计方法，确定了具有理想γ-分泌酶调节作用的 4-氨甲基苯乙酸 4。通过支架优化，发现了具有改善的脑穿透性的新型化学系列，以 6b 为代表。进一步的 SAR 研究提供了具有良好药理特性的类似物 6q。口服 6q 可显著降低小鼠和大鼠脑中的 Aβ42 水平。
