Demystifying Brain Penetration in Central Nervous System Drug Discovery

被引：228

作者：

Di, Li ^{[1
]}

Rong, Haojing ^{[1
]}

Feng, Bo ^{[1
]}

机构：

[1] Pfizer Inc, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 01期

关键词：

CANCER RESISTANCE PROTEIN; POSITRON-EMISSION-TOMOGRAPHY; P-GLYCOPROTEIN EXPRESSION; IN-VIVO; RECEPTOR OCCUPANCY; UNBOUND CONCENTRATION; PERFUSION TECHNIQUE; PERMEABILITY ASSAY; LEAD OPTIMIZATION; CACO-2; CELLS;

D O I：

10.1021/jm301297f

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

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页码：2 / 12

页数：11

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