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

• Published in: European journal of medicinal chemistry Vol. 182; p. 111643
• Main Authors: Freeman, Burgess B., Yang, Lei, Rankovic, Zoran
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.11.2019
• Subjects: Animals; BBB; Blood-Brain Barrier - drug effects; Brain; Central Nervous System - drug effects; Central Nervous System Agents - chemistry; Central Nervous System Agents - pharmacology; CNS; Drug Delivery Systems; Drug design; Drug Discovery; Free drug hypothesis; Humans; Molecular Structure; Penetration; Pharmacokinetics; Structure-Activity Relationship; Brain; Free drug hypothesis; BBB; Penetration; CNS; Drug design; Pharmacokinetics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111643

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. [Display omitted] •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.