title: Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors.
abstract: The influence of physicochemical properties, including lipophilicity, H-bonding capacity and molecular size and shape descriptors on brain uptake has been investigated using a selection of marketed CNS and CNS-inactive drugs. It is demonstrated that the polar surface area of a drug can be used as a suitable descriptor for the drugs' H-bonding potential. A combination of a H-bonding and a molecular size descriptor, i.e., the major components of lipophilicity and permeability, avoiding knowledge of distribution coefficients, is proposed to estimate brain penetration potential of new drug candidates. Previously reported experimental surface activity data appear to be strongly correlated to molecular size of the drug compounds. Present analysis offers a modern basis for property-based design and targeting of CNS drugs.
authors.affiliation: F. Hoffmann-La Roche Ltd, Pharma Research-Molecular Design and Bioinformatics, Basel, Switzerland. han_waterbeemd@sandwich.pfizer.com
authors.forename: H
authors.initials: H
authors.lastname: van de Waterbeemd
authors.forename: G
authors.initials: G
authors.lastname: Camenisch
authors.forename: G
authors.initials: G
authors.lastname: Folkers
authors.forename: J R
authors.initials: JR
authors.lastname: Chretien
authors.forename: O A
authors.initials: OA
authors.lastname: Raevsky
mesh_terms: D001812:Blood-Brain Barrier / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D006860:Hydrogen Bonding; D015394:Molecular Structure; D008970:Molecular Weight; D010599:Pharmacokinetics; D012995:Solubility; D013223:Statistics as Topic