Demystifying brain penetration in central nervous system drug discovery. Miniperspective.
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.
Pfizer Inc., Groton, Connecticut 06340, USA. Li.Di@Pfizer.com
Li
L
Di
Haojing
H
Rong
Bo
B
Feng
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D055808:Drug Discovery; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D010539:Permeability; D011485:Protein Binding
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001798:Blood Proteins; D002491:Central Nervous System Agents; D009363:Neoplasm Proteins