Designing CNS Drugs for Optimal Brain Exposure
Zoran Ranković · 2015
The great majority of CNS drugs are small molecules that are designed to cross the blood–brain barrier (BBB) via the transcellular passive diffusion route. Achieving optimal brain exposure is a unique and major challenge for medicinal chemists working on the CNS targets. Design strategies toward such molecules and their physicochemical properties are the main foci of this chapter. The existence of the BBB renders classic pharmacokinetic (PK) parameters, such as oral bioavailability and plasma concentration, insufficient for assessing CNS drug candidates due to uncertainty regarding whether such parameters will reflect the time course or exposure levels in the brain. Several key physicochemical properties have been identified that influence the rate of brain permeability and the extent of brain penetration including H-bonding potential, molecular weights (MWs), lipophilicity, polar surface area (PSA), ionization state, and rotatable bond count.