Strategies to minimize CNS toxicity: in vitro high-throughput assays and computational modeling

Abstract

Introduction: Healthy functioning of the brain is dependent on the ability of the blood–brain barrier (BBB) and other central nervous system (CNS) barriers to protect the neurocompartments from potential disruptive and damaging xenobiotic agents. In vitro high-throughput (HT) screens and computational models that assess a compound's ability to pass through or disrupt the BBB have become important tools in the identification of new well-tolerated peripheral drugs and safer chemical products such as pesticides. Leveraging these HT in vitro assays and computational BBB tools together with the current understanding of brain penetration may enable the drug discovery community to minimize access of drug candidates into the CNS compartment.

Areas covered: This article reviews aspects of the most recent in vitro and computational approaches designed to provide an early assessment of a compound's ability to access the neurocompartment. This article also provides insight into using these tools to identify compounds that have restricted access to the neurocompartment.

Expert opinion: The development of safer peripheral-acting medicines and chemical products can be achieved through prospective design and early assessment with HT assays of the BBB in conjunction with computational models. Exclusion or significantly reduced access of a compound to the neurocompartment will increase the odds of identifying a compound with reduced CNS-related adverse drug reactions. A holistic approach to compound design and evaluation that incorporates prospective design principles (e.g., optimization of physicochemical properties), leverages HT in vitro assays and integrates the use of BBB computational models may yield the ‘best-in-class’ peripherally acting product.

Keywords::

• adenosine triphosphate binding cassette (ABC) transporters
• adverse drug reaction
• blood–brain barrier
• brain availability
• CNS toxicity
• high-throughput screens
• p-glycoprotein
• physicochemical properties
• physiologically based pharmacokinetic modeling

Notes

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