title: Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity.
abstract: Here, we review the performance of chromatographic hydrophobicity measurements in a data set of 100,000 GlaxoSmithKline compounds, demonstrating the advantages of the method over octanol-water partitioning and highlighting new insights for drug discovery. The value of chromatographic measurements, versus other hydrophobicity estimates, was supported by improved relationships with solubility, permeation, cytochrome P450s, intrinsic clearance, hERG binding and promiscuity. We also observed marked differentiation of the relative influence of intrinsic and effective hydrophobicity. The summing of hydrophobicity values plus aromatic ring count [logD(pH7.4) (or logP)+#Ar], indicated a wide relevance for simplistic 'property forecast indices' in developability assays, clearly enhanced by chromatographic values; therefore establishing new foundations for enriching property-based drug design.
authors.affiliation: Department of CSC Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, SG1 2NY, UK. Rob.J.Young@gsk.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
authors.forename: Darren V S
authors.initials: DV
authors.lastname: Green
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Luscombe
authors.forename: Alan P
authors.initials: AP
authors.lastname: Hill
mesh_terms: D002845:Chromatography / Q000379:methods*; D019411:Clinical Laboratory Techniques / Q000379:methods*; D015195:Drug Design; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility
chemical_list: D006841:Hydrocarbons, Aromatic; D004364:Pharmaceutical Preparations