How to Get Drugs Into the Brain

By Dennis Koester
Reviewed and edited by Michael Walters and Dennis Hu

Obtaining adequate drug exposure in the brain is key to treating CNS diseases effectively. Recently, Dennis Koester gave us a crash course in CNS drug discovery in a Drug Hunter Flash Talk. Here, he sums up some key points on how to find compounds that cross the blood-brain barrier, including:

1. How to Get Drugs Into the Brain
2. The Blood-Brain Barrier, Gatekeeper of the Brain
3. What Makes a Compound Brain-Penetrant? The Transporter Problem
4. Aim for High Passive Permeability While Avoiding Efflux Transporters
5. What is K_p,uu? Why K_p,uu is the Most Important Parameter in CNS Drug Discovery
6. What Influences the K_p,uu of Drugs?
7. Tools for Predicting Brain Penetration
8. In Vitro Assays for Evaluating Permeability and Efflux
9. Harnessing In Silico and In Vitro Data to Predict K_p,uu in CNS Drug Discovery
10. Optimize for Unbound Brain Concentration, not Unbound Fraction
11. Examples of Improved Brain Exposure from CNS Drug Discovery
12. Key Guidelines for CNS Drug Discovery

How to Get Drugs Into the Brain

Drug discovery for the CNS (central nervous system) poses a unique set of challenges due to the complexity and selective permeability of the BBB (blood-brain barrier). This article will discuss various molecular design strategies for reducing BBB efflux and increasing passive permeability. We will also explore some general approaches for CNS drug discovery, including in silico tools to predict brain penetration, in vitro assays for monitoring drug discovery programs, and in vivo methods for determining unbound partition coefficients. Finally, we provide a case study on HAT (Human African Trypanosomiasis), a CNS disorder, to demonstrate how these strategies can be applied to specific cases.

The Blood-Brain Barrier, Gatekeeper of the Brain