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Background & Objective: Compound X is a drug candidate for the treatment of neurodegenerative diseases. Its brain distribution was evaluated as part of the lead identification and optimization of early drug discovery. Methods: The brain distribution of compound X was studied in genetic transporter knockout rodent models, in vivo models with a chemical inhibitor and in vitro transporter cell systems. Results: Compound X was found to be a substrate for human Breast Cancer-Resistance Protein (BCRP) in vitro (efflux ratio 8.1) and rodent Bcrp in vivo (Kp,uuKO/Kp,uuWT = 0.15/0.057 = 2.7, p < 0.05) but not a substrate for human P-glycoprotein (P-gp) in vitro (efflux ratio 1.0) nor rodent P-gp in vivo (Kp,uuKO/Kp,uuWT = 0.056/0.051 = 1.1, p > 0.05). When both transporters were knocked out in vivo, Kp,uu increased to 0.51 ± 0.02. Similar patterns observed across compounds with related chemistry corroborated structure-activity relationship. Conclusion: While in vitro assays showed compound X to be a substrate for human BCRP and not P-gp, in vivo studies indicated a synergistic effect between rodent efflux transporters. However, this only accounted for ~50% of restricted BBB-transport, suggesting involvement from other efflux transporters. Given Kp,uu is a key criterion for assessing technical quality of CNS candidates before progression into clinical development, it is important to identify relevant screening assays for a better understanding of low Kp,uu and brain distribution in pre-clinical models for translation to humans.

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