Nugiel D A, Voss M E, Brittelli D R, Calabrese J C
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0353, USA.
Drug Des Discov. 1995 Apr;12(4):289-95.
A novel series of cognition enhancers was designed based on molecular modeling and X-ray structure analysis of EXP-9121 (2). This new series features a spirocyclic ring system that constrains the side chain substituents into the orientation seen in the X-ray crystal structure of 2. MM2 calculations preformed on 2 accurately predicted the solid state conformation. Compounds could be rapidly assembled using a bis-Michael addition reaction. Unfortunately, in vitro testing showed moderate activity at best, suggesting the X-ray structure of 2 does not mimic the bioactive conformation.
基于EXP-9121（2）的分子建模和X射线结构分析，设计了一系列新型认知增强剂。这个新系列的特点是具有一个螺环系统，该系统将侧链取代基限制在2的X射线晶体结构中所见的方向。对2进行的MM2计算准确地预测了固态构象。化合物可以通过双迈克尔加成反应快速组装。不幸的是，体外测试显示其活性充其量为中等，这表明2的X射线结构并不能模拟生物活性构象。
