Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery

摘要: The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties new chemical entities (NCEs), thereby optimizing routine evaluation selection novel neurotherapeutics. Forty compounds covering a wide range physicochemical various CNS targets were investigated. combinatory mapping approach used for assessment extent blood-brain cellular barriers transport via estimation unbound-compound brain (Kp,uu,brain) cell (Kp,uu,cell) partitioning coefficients. Intra-brain distribution evaluated using slice method. Intra- sub-cellular estimated calculation unbound-drug cytosolic lysosomal Assessment Kp,uu,brain revealed extensive variability in penetration across compounds, prevalence actively effluxed at barrier. Kp,uu,cell valuable identification tendency accumulate intracellularly. Prediction provided insight into subcellular accumulation. Integration neuroPK parameters pharmacodynamic readouts demonstrated value proposed target engagement NCE selection. With rather easily-performed approach, it possible provide quantitative information supporting decision making drug discovery setting.