Demystifying Brain Penetrationin Central NervousSystem Drug Discovery.

This Perspective provides important concepts about theblood–brainbarrier (BBB) in drug discovery and how they should be applied effectivelyin designing successful CNS drugs. Key parameters for brain penetrationare discussed, including unbound brain concentration, unbound brain-to-plasmaratio, BBB permeability, fraction unbound in brain and plasma, andtransporters. Results from a retrospective analysis of 32 Pfizer CNSclinical drug candidates are described. Frequently encountered misconceptionsabout brain penetration in drug discovery programs are clarified.Strategies and guidance are provided to enhance or minimize brainexposure for CNS or peripheral targets, respectively. Recommendationsfor screening methodologies and a cascade in assessing brain penetrationpotential are presented. [ABSTRACT FROM AUTHOR]