Synthesise a CNS drug that can cross the blood brain barrier?

Central nervous system (CNS) drugs include analgesics, sedatives, and anticonvulsants, with drugs being used to treat the effects of a wide variety of medical conditions such as Alzheimer’s disease, Parkinson’s disease, and depression. More than 1 billion people globally suffer from a CNS disease, with one in five Americans taking at least one psychiatric drug. In the US and Europe combined, the overall cost of the economic burden of CNS diseases is estimated to be more than $2 trillion, with that figure expecting to triple by 2030 (1). Whilst most pharmaceutical companies are patient centric, these figures are financially appealing. However, development of therapies for CNS diseases has lagged behind that for other therapeutic areas. CNS drugs can take more than 20 months longer to develop than other drugs, with attrition rates greater than 50%. These failures can be attributed to a number of reasons such as inadequate dosage to hit the therapeutic target, high placebo effect, high patient dropout rate, inaccuracies of preclinical disease models, and incomplete understanding of brain disease mechanisms. (1)

One of the challenges of working on a CNS drug discovery project is for the drug to traverse the blood-brain barrier (BBB). The BBB protects the brain from most pathogens, sheltering it from the systemic circulation. It also prevents most large molecule neurotherapeutics and more than 98% of all small molecule drugs reaching the brain from the bloodstream, the tight junctions of the endothelial cells lining brain capillaries restricting paracellular movement of substances across the BBB. The BBB serves roles other than that of blocking circulating substances from entering the CNS. It also facilitates and regulates the entry of many substances that are critical to CNS function and secretes substances into the blood and CNS. These extra-barrier functions allow the BBB to influence the homeostatic, nutritive, and immune environments of the CNS and to regulate the exchange of informational molecules between the CNS and blood. (3)

High attrition rates of preclinical and clinical drug candidates led Wager et al (4) to design a tool based on key physicochemical properties (clogP, clogD, molecular weight, topological polar surface area, hydrogen bond donors, and pKa) that would enable multiparameter optimisation (MPO) of druglike properties to accelerate the identification of drug candidates with optimal pharmacokinetic and safety profiles. After nearly 8 years of using this tool at Pfizer, Wager et al have reported a reduction in the number of compounds submitted to exploratory toxicity studies and an increase in the survival of the CNS MPO candidates through regulatory toxicology into first in human studies. (5) The tool has also been used outside of Pfizer to reduce attrition and improve compound quality in the design phase.

An understanding of the barrier and extra-barrier aspects of BBB physiology is also critical to developing drugs that can access the CNS. A recent CNS paper by Patel et al (6) discusses several key approaches for brain targeting including physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). These alternative approaches look promising.

The Canadian company Angiochem is using a physiological approach to gain entry across the BBB. They have engineered ANG1005, an Angiopep-2 paclitaxel conjugate to gain entry into the brain by targeting lipoprotein receptor-related protein (LRP-1), which is one of the most highly-expressed receptors on the surface of the BBB.  Once inside the brain, ANG1005 enters tumour cells using the same receptor-mediated pathway through LRP-1, which is upregulated in various cancer cells including malignant glioma and metastatic cancers in the brain. (7) Phase II data presented in October 2016 shows ANG1005 has demonstrated clinical benefit, both intracranially and extracranially in pre-treated breast cancer patients with recurrent brain metastases. (8)

Blog written by Kamlesh Bala





(4) ACS Chem Neurosci. 2010 Jun 16;1(6):435-49

(5) ACS Chem. Neurosci. 2016, 7, 767−775

(6) Patel, M.M. & Patel, B.M. CNS Drugs (2017).





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.