blood brain schema

Perhaps the hardest medicinal chemistry challenge is taking a series of compounds, and modifying them, so they pass through the blood brain barrier. Such drug discovery projects have enlarged testing cascades, and usually require an early in-vitro absorption assay, and secondary rodent pharmacokinetics experiments to measure concentration of drug in the brain compartment. As such the cycle times around the Design-Make-Test-Analyse are protracted. The need for clear understanding of the processes involved, and the properties required in molecules, to reduce the number of cycles is paramount. We selected the review “Demystifying brain penetration…” as this gives a broad summary of the understanding so far.

Demystifying brain penetration in central nervous system drug discovery.

J. Med. Chem. 2013, 56, 2−12. 

In recent years the “CNS MPO” score, which can be calculated at the point of design, has gained popularity, so it is worth referencing this paper too.

Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties

ACS Chem. Neurosci. 2010, 1, 435–449


However, the CNS MPO score might become dated, as further understanding of the transporters involve rises. It might be that the count of number of Hydrogen Bond Donor (HBD) might be the key predictor.

How hydrogen bonds impact P-glycoprotein transport and permeability.

Bioorg. Med. Chem. Lett. 2012, 22, 6540−6548.

And lastly a couple of medchem papers on series that were optimised for CNS penetration:

The design and identification of brain penetrant inhibitors of phosphoinositide 3- kinase α.

J. Med. Chem. 2012, 55, 8007−8020.

Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice

J. Med. Chem. 2014, 57, 970−986

A couple of more papers suggested by Pete Kenny.

CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure
J. Med. Chem. 2015, 58, 2584–2608

Structural Modifications that Alter the P-Glycoprotein Efflux Properties of Compounds
J. Med. Chem. 2012, 55, 4877–4895

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