Demystifying Brain Penetration in Central Nervous System Drug Discovery
Demystifying Brain Penetration in Central Nervous System Drug Discovery
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DOI：
10.1021/jm301297f
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发表时间：
2013-01-10
影响因子：
7.3
通讯作者：
Feng, Bo
中科院分区：
文献类型：
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作者：
Di, Li;Rong, Haojing;Feng, Bo
这一视角提供了有关药物发现中血脑屏障(BBB)的重要概念，以及如何有效地将它们应用于设计成功的中枢神经系统药物。讨论了影响脑渗透的关键参数，包括游离脑浓度、游离脑浆比、血脑屏障通透性、脑内和血浆中游离分数以及转运蛋白。对32个辉瑞中枢临床候选药物的回顾性分析结果进行了描述。澄清了在药物发现计划中经常遇到的关于脑渗透的误解。提供了相应的策略和指导，以增加或减少中枢神经系统或外周靶点的脑暴露。提出了筛选方法的建议和评估脑渗透潜力的级联。
This Perspective provides important concepts about the blood-brain barrier (BBB) in drug discovery and how they should be applied effectively in designing successful CNS drugs. Key parameters for brain penetration are discussed, including unbound brain concentration, unbound brain-to-plasma ratio, BBB permeability, fraction unbound in brain and plasma, and transporters. Results from a retrospective analysis of 32 Pfizer CNS clinical drug candidates are described. Frequently encountered misconceptions about brain penetration in drug discovery programs are clarified. Strategies and guidance are provided to enhance or minimize brain exposure for CNS or peripheral targets, respectively. Recommendations for screening methodologies and a cascade in assessing brain penetration potential are presented.