Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept

Abstract

Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood-brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic.

Assessing molecular scaffolds for CNS drug discovery

“…Whilst neither system was intended solely as a prediction of BBB permeation, pMPO was able to better predict efflux liabilities for a set of 500 randomly chosen compounds from the Merck compound collection, particularly for compounds with low efflux ratios (<2). Both tools add value in the optimisation of CNS leads that must satisfy criteria including solubility, permeability, safety and the myriad of factors that may influence brain penetration [18,19].…”

Pharmacogenomics Dictate Pharmacokinetics: Polymorphisms in Drug-Metabolizing Enzymes and Drug-Transporters

“…For numerous diseases of the central nervous system (CNS), e.g. gliomas, AIDS dementia, epilepsy, etc., drug absorption into the brain has been a significant problem (Aragon-Ching JB, 2007;Reichel A. 2009).…”

Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676

“…Given the complexity of the brain and cerebral vasculature, one of the main challenges in the development of efficacious CNS drugs is to predict brain exposure and target engagement based primarily on drug affinity in vitro, animal behavior data, and drug concentrations in plasma (Liu et al, 2005;Summerfield and Jeffrey, 2006;Reichel, 2009).…”