Estimation of the blood-brain barrier (BBB) permeability has long been a topic of major interest for the design of drugs with an intended pharmacological action in the central nervous system(CNS).Presently, a handful of in vitro transporter assays and animal neuropharmacokinetics (neuroPK) studies have been developed to support the lead optimization and discovery process.A variety of in silico approaches have also been widely utilized, ranging from simple physicochemical rules to quantitative structure-activity relationship (QSAR) models.However, there are still gaps in our knowledge of ① the connection between human derived CNS-accessible chemical space and the neuro PK data from preclinical species.② the interpretability of the selected physicochemical descriptors.③ the correlation of human in vitro P-glycoprotein (P-gp) efflux ratio (ER) and the rodent unbound brain-to-blood ratio (Kp,uu, the most relevant predictor for BBB penetrability).