title: Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration.
abstract: Optimising drug properties can be an important strategy to limit penetration into the CNS and offers advantages in reducing the risk of undesirable neurological effects        When considering the design of these drugs it is important to consider the relative influx and efflux rates at the relevant biological membranes        The highest degree of restriction at the brain is probably achievable by utilising active transport to exclude compounds from the brain        Affinity for the efflux transporters Pgp and BCRP has been achieved in two in-house chemistry programmes by increasing polar surface area, which resulted in highly orally bioavailable low CNS penetrant compounds in preclinical species.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, UK. scole2412@aim.com
authors.forename: Susan
authors.initials: S
authors.lastname: Cole
authors.forename: Sharan
authors.initials: S
authors.lastname: Bagal
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.forename: Katherine
authors.initials: K
authors.lastname: Fenner
authors.forename: Tanya
authors.initials: T
authors.lastname: Hay
authors.forename: Sarah
authors.initials: S
authors.lastname: Kempshall
authors.forename: Graham
authors.initials: G
authors.lastname: Lunn
authors.forename: Manthena
authors.initials: M
authors.lastname: Varma
authors.forename: Paul
authors.initials: P
authors.lastname: Stupple
authors.forename: William
authors.initials: W
authors.lastname: Speed
mesh_terms: D001812:Blood-Brain Barrier / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects*; D004339:Drug Compounding / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations