Practical approaches to evaluating and optimizing brain exposure in early drug discovery

Developing drugs for CNS related diseases continues to be one of the most challenging endeavors in drug discovery. This is at least in part related to the existence of the Blood Brain Barrier (BBB), a complex multicellular organization that provides selective access to required nutrients and hormones, while removing waste and restricting exposure to potential harmful toxins, pathogens, and xenobiotics. Consequently, designing and selecting molecules that can overcame this protection system are unique and critical aspects of the CNS drug discovery. Here we review modern CNS pharmacokinetic concepts and methods suitable for early drug discovery, and medicinal chemistry strategies towards molecules with optimal CNS exposure. • Drug unbound concentrations are more predictive of target occupancy and in vivo efficacy. • The BEA is the most commonly used approach in early drug discovery for evaluation of compound in vivo CNS drug properties. • CNS drugs tend to be smaller molecules with higher lipophilicity and lower PSA than non-CNS drugs. • Reducing HBD capacity is one of the most frequently reported drug designing strategies for enhancing brain exposure.