Department of Neuroscience Discovery Chemistry, Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2011 Nov 15;21(22):6916-24. doi: 10.1016/j.bmcl.2011.06.109. Epub 2011 Jun 30.
The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.
讨论了一类γ-内酰胺1,3-二氨基丙醇过渡态类似物抑制剂的合成、评价和构效关系。介绍了两种优化先导化合物 1a 的策略。缩小抑制剂的整体大小导致了γ-内酰胺 1i 的鉴定，而在抑制剂的前侧引入构象约束则产生了 3-羟基吡咯烷抑制剂 28n 等化合物。呈现了 1i 在大鼠和 28n 在 Tg 2576 小鼠中的完整体内特征。
