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

Eur J Med Chem. 2019 Nov 15:182:111643. doi: 10.1016/j.ejmech.2019.111643. Epub 2019 Aug 23.

Abstract

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.

Keywords: BBB; Brain; CNS; Drug design; Free drug hypothesis; Penetration; Pharmacokinetics.

Publication types

  • Review

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Central Nervous System / drug effects*
  • Central Nervous System Agents / chemistry
  • Central Nervous System Agents / pharmacology*
  • Drug Delivery Systems
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Central Nervous System Agents