Among the most devastating disorders of our time, neurologic and psychiatric diseases combine to cause more disability than any other disease area. Access to the central nervous system (CNS) is essential for most neuro-therapeutics to elicit their effects. One of the key objectives within the medicinal chemistry discipline is to design molecules that penetrate into the target tissue. The objective of tissue specificity can be to gain or restrict drug access to the compartment of interest. In brain tissue targeting, the active transport proteins such as P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) are key components of the blood brain barrier (BBB) and it has been well established that drug candidates with high efflux ratios (ER) of these proteins have poor penetration into brain tissue. In the current work, we describe our efforts of leveraging design strategies by harnessing structural and physicochemical properties assessment coupled with the P-gp and BCRP transporters’ impact in determining brain penetration and its translation from rodent to human brain tissue targeting. This work will include our investigations of alternate MDR-MDCK cell lines as better predictions of brain penetration and establishment efforts of a correlation between <i>in vitro</i>, rodent data, non-human primate (nhp), and human <i>in vivo</i> data.

Harnessing preclinical data as a predictive tool for human brain tissue targeting

2019 Fall National Meeting

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