Central nervous system (CNS) diseases are a major focus of the pharmaceutical industry, with CNS drugs representing some of its most successful products. These include Pfizer’s Zoloft, Eli Lilly’s Cymbalta, and Abilify from Bristol-Myers Squibb and Otsuka.
Drug discovery and development researchers, however, have experienced difficulty developing CNS drugs that can complete clinical trials and win regulatory approval. This is especially true for drugs that address major unmet needs in the CNS area such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), stroke, brain cancers, and metastases to the brain.
A major bottleneck in successful development of CNS drugs is the discovery or design of drugs that can cross the blood-brain barrier (BBB).
Researchers believe that the function of the BBB is to protect the CNS from toxic molecules, including toxins that may be ingested in food, and endogenously formed toxic molecules. Unfortunately, the BBB also serves as a barrier to potentially beneficial drugs for treatment of CNS diseases. About 98% of small molecule drugs fail to cross the BBB and, no large molecule drugs cross the BBB, except for a few natural peptides and proteins such as insulin, and those specifically designed to do so.
Most current CNS drugs are small molecule drugs that cross the BBB via passive diffusion. These drugs are either old compounds that were discovered via traditional drug discovery methods (involving serendipity and animal studies), or newer drugs discovered via high-throughput screening (HTS) and medicinal chemistry.
Small molecule drugs that can cross the BBB via passive diffusion must have physicochemical properties that allow them to do so. Such drugs have a more restricted set of physicochemical properties than the universe of oral drugs. For example, the molecular weight cutoff for CNS penetrant drugs appears to be 400 daltons, as opposed to 500 daltons for all drug-like compounds. Companies such as Pfizer and GlaxoSmithKline have developed computational models, based on the physicochemical properties of compounds, which allow medicinal chemists to predict the ability of small molecule drugs to cross the BBB via passive diffusion, and to design compounds that can do so.
A particular challenge to the development of CNS-penetrant small molecule drugs is the action of efflux transporters. These are a class of ATP-dependent membrane glycoproteins that actively expel molecules that have crossed the BBB back across endothelial cell membranes and out of the brain. Researchers consider the P-glycoprotein (P-gp) to be the most important of these transporters. In addition to designing compounds that have the physicochemical properties needed to enable passive diffusion across the BBB, medicinal chemists must also ensure that these compounds are poor substrates for P-gp.
Small molecule compounds that are designed to cross the BBB via passive diffusion seem to be particularly ill-suited to address tempting new disease targets in indications with high unmet need. For example, researchers have identified the enzyme beta-secretase as being critically involved in the amyloid pathway of Alzheimer’s disease. Because of the physicochemical nature of the active site of beta-secretase, it is difficult to design small molecule inhibitors that readily cross the BBB via passive diffusion.