Department of Medicinal Chemistry, Elan Pharmaceuticals , 180 Oyster Point Boulevard, South San Francisco, California 94080, United States.
J Med Chem. 2013 Jul 11;56(13):5261-74. doi: 10.1021/jm301741t. Epub 2013 Jun 20.
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.
在此，我们介绍了设计代谢稳定的γ-分泌酶抑制剂的策略，这些抑制剂选择性地抑制 Aβ 的产生而不影响 Notch。我们强调了我们用于引入多样性和手性的合成策略。化合物 30（ELND006）和 34（ELND007）都进入了人体临床试验。描述了这两种化合物的体外和体内特性。比较了化合物 30、34、Semagacestat 41、Begacestat 42 和 Avagacestat 43 在小鼠体内抑制 Aβ 生成的情况。30 降低了健康人类志愿者脑脊液中的 Aβ。
