Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character
Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character
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DOI：
10.1021/acsmedchemlett.0c00039
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发表时间：
2020-06-11
影响因子：
4.2
通讯作者：
Bloomfield, Graham
中科院分区：
文献类型：
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作者：
Cox, Brian;Zdorichenko, Victor;Bloomfield, Graham
向患者提供新药的压力随着化合物失败率的增加而继续沿着增长，从而使当前的研发模式处于危险之中。分析表明，增加潜在候选药物的三维性降低了失败的风险，并提高了结合的选择性和频率。由于这个原因，许多工作者已经把光化学的力量作为一种手段，以产生新的sp（3）丰富的支架用于药物发现计划的新的眼光。在这里，我们报告的设计，合成和计算结构分析的一系列2，4-methanoprolines具有固有的3D字符（PMI和PBF分数）显着高于更广泛的AbbVie规则3（Ro 3）的集合。
The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp(3) rich scaffolds for use in drug discovery programs. Here we report the design, synthesis, and computational structural analysis of a series of 2,4-methanoprolines having inherent 3D character (PMI and PBF scores) significantly higher than that of the broader AbbVie Rule of 3 (Ro3) collection.