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).




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