title: Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates.
abstract: In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood-brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (Kp,uu,brain), intracellular accumulation (Kp,uu,cell), and binding and distribution in the brain (Vu,brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties.
authors.affiliation: Translational PKPD Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab, Uppsala University , Uppsala, Sweden.
authors.forename: Irena
authors.initials: I
authors.lastname: Loryan
authors.forename: Vikash
authors.initials: V
authors.lastname: Sinha
authors.forename: Claire
authors.initials: C
authors.lastname: Mackie
authors.forename: Achiel
authors.initials: A
authors.lastname: Van Peer
authors.forename: Wilhelmus H
authors.initials: WH
authors.lastname: Drinkenburg
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.forename: Donald
authors.initials: D
authors.lastname: Heald
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
authors.forename: Carola M
authors.initials: CM
authors.lastname: Wassvik
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D015233:Models, Statistical; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002491:Central Nervous System Agents
keywords: BBB drug transport; PLS analysis; binding and distribution in the brain; blood−brain barrier (BBB); brain drug delivery; in silico modeling; intracellular accumulation; neuropharmacokinetics