Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2013 Aug 15;23(16):4674-9. doi: 10.1016/j.bmcl.2013.06.006. Epub 2013 Jun 11.
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.
构象限制羟乙基胺（HEA）BACE 抑制剂的主要区域的结构活性关系描述如下。P1'区域的变化提供了对 Cat-D 的选择性，一系列 2,2-二氧代异硫代色满和优化色满-HEA(s)的 P2'取代基与极性取代基提供了化合物的体外渗透性的提高。当在色满的 C-2 位置放置小的脂肪族取代基如甲基、正丙基和环丙基时，观察到显著的效力增益。
