Smuggling drugs into the brain: old and new tricks


Figure 1. Proposed mechanisms of transport across the blood-brain barrier

Every medicinal chemist involved in neuroscience drug discovery has experienced the joys and pains of the blood brain barrier (BBB), classically defined as the system of tight junctions between the epithelial cells of the brain capillaries that strictly regiment the access of molecules into the CNS.

As medicinal chemists, we usually picture the BBB as a more impenetrable version of other biological interfaces and consequently we design our CNS-penetrant molecules applying more rigid physicochemical filters. Additionally, we use in vitro brain permeability models that tend to focus only on passive diffusion and efflux.

In reality big and polar molecules, antibodies and viruses have the ability of crossing or eluding the BBB using a number of ‘side entrances’.

In the last 30 years the understanding of the BBB mechanisms has increasingly gained clarity and accordingly many new opportunities for drug delivery into the brain have been tested. These new opportunities usually exploit existing mechanisms utilised by endogenous molecules that need to gain access to the brain (e.g. nutrients, aminoacids, regulatory blood proteins) or tricks invented by pathogens. Old and new ways of crossing the BBB have been recently reviewed by William A. Bank in the April issue of Nature Reviews Drug Discovery (doi:10.1038/nrd.2015.21).

Some of the most interesting and overlooked pathways include:

Access via influx (blood-to-brain) transporters – this is an old strategy for drug delivery (e.g. L-dopa, gabapentin which use transporters for neutral aminoacids). More recently this mechanism has been considered for selective delivery to targeted areas of the brain.

‘Trojan Horse strategies  –  where a therapeutic agent (cargo) is conjugated to a ligand (Trojan Horse) of a particular influx transporter expressed on the luminal membrane (blood-side). The complex in usually routed on the abluminal membrane (brain-side) by transcytosis.

Absorptive transcytosis – another vesicle-based pathway often used by penetrating peptides and antibodies fragments.

Extracellular pathways or functional leaks – these are anatomically defined areas of the brain that are deficient in blood brain barrier and as such allow controlled access to small amount of serum proteins including albumin and immunoglobulins. It has been suggested that antibodies – with low volume of distribution and high circulating half-life – can enter the CNS using this way.

Many small molecules and biologics that exploit these or similar tricks are being validated in the clinic.

Nevertheless, these mechanisms are quite difficult to predict and permeability models available to medicinal chemists for rational design are unfortunately still very rudimental…


Figure 1 adapted from: Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier; Julia V. Georgieva et al. Pharmaceutics 2014, 6, 557-583; doi:10.3390/pharmaceutics6040557


Blog written by Alessandro Mazzacani


Central Nervous System Drug Discovery For Dummies

The Pfizer neuroscience group have published several papers over the recent years which have tried to simplify the complexities involved with successful design of CNS-penetrating drugs.  The CNS MPO papers – ‘Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties’ and ‘Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes’ whilst being additions to the battery of rules/guidelines with which to beat medicinal chemists have also provided some practical tools for assessing the ‘CNS drug-likeness’ across a range of potential chemical series and structures in early project phases.

A recent perspective in J Med Chem ‘Demystifying Brain Penetration in Central Nervous System Drug Discovery’ continues this theme, but unlike the papers above, does not provide any significant analysis of data, but instead is a slightly strange article to find in this journal, as it essentially provides a glossary of terms for CNS PK and a reiteration of the basic concepts of CNS drug discovery.  However, that being said, this compilation of terms covering compartments, transporters, assays and general principles should provide a useful recap for anyone working in the field.

The concepts described cover unbound drug concentrations, unbound & total brain-to-plasma ratios, fraction unbound, BBB passive permeability and efflux ratios:

And then explores these parameters across a retrospective analysis of 32 Pfizer CNS clinical drug candidates according to the flow scheme in Figure 2 within the paper.  These compounds partitioned into 14 each in Groups I and II and 4 in Group III.  The flow analysis and subsequent conclusions that Group I are best to progress are not exactly surprising, although it would be interesting to know what confidence building measures enabled the progression of the molecules in Group III…?  The motivation for highlighting this paper, however, lies in the section ‘Clarification of Misconceptions about the BBB’ which is essentially the debunking of 8 CNS drug discovery urban myths which are claimed to be regularly encountered.  This does provide helpful material to combat the continuing obsession with brain/plasma ratios, and reiterates the need to focus instead on the ratio of unbound brain/plasma concentrations as the meaningful parameter against which to optimise.

Additionally, the clarification of the use of CSF is helpful, for which the authors state that the CSF drug concentration can sometimes be a surrogate for unbound drug concentrations in the brain, but these data can be misleading, particularly for drugs which are actively transported (P-gp at blood-CSF barrier pumps into CSF in contrast to P-gp in blood-brain barrier).  Finally, the data from across the Pfizer compound set was used to make the valuable observation that CNS PK in higher species did not increase the confidence of achieving good CNS penetration in man and that the rodent PK alone was sufficient for pre-clinical evaluation.