Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States.
Bioorg Med Chem Lett. 2010 Jan 15;20(2):632-5. doi: 10.1016/j.bmcl.2009.11.052. Epub 2009 Nov 20.
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.
8,8-二苯基-2,3,4,8-四氢咪唑并[1,5-a]嘧啶-6-胺（1）通过高通量筛选（HTS）被鉴定为 BACE1 的弱（微摩尔）抑制剂。X 射线晶体学研究表明，2-氨基咪唑环与 BACE1 催化位点中的天冬氨酸 32 和天冬氨酸 228 形成关键氢键相互作用。使用基于结构的聚焦文库进行的先导化合物优化导致发现了低纳摩尔级的 BACE1 抑制剂，如 20b，其取代基从 S1 到 S3 口袋延伸。
