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Feb 1, 2009 (Vol. 29, No. 3)

Strategies to Overcome Blood-Brain Barrier

Complex Biology of CNS Diseases Continues to Hamper Development of Effective Drugs

  • 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.

  • Nutrient Transporter

    Click Image To Enlarge +
    Figure 1. Dopamine cannot cross the BBB.

    Researchers have been developing novel technologies that enable the design of drugs that cross the BBB via active transport. The permeation of the brain by drugs that are actively transported across the BBB is approximately an order of magnitude greater than for compounds that cross the BBB via passive diffusion. Moreover, most small molecule compounds do not cross the BBB at therapeutically significant concentrations at all. This problem might be overcome by developing versions of these compounds that can be actively transported across the BBB.

    One technology for enabling active transport of small molecule drugs across the BBB involves targeting endogenous nutrient transporters. These transporters are members of the solute carrier (SLC) transporter superfamily. Transport of small molecules across the BBB by these membrane proteins is known as carrier-mediated transport (CMT).

    CMT is responsible for transport of such nutrients as glucose, other sugars, lactate, nucleosides, fatty acids, and vitamins, as well as certain hormones (such as thyroid hormones) into the brain. These substances are vital for brain function. Many of the SLC transporters found in brain endothelium that are involved in CMT are also found in intestinal endothelium, where they are involved in transport of nutrients—and drugs—from the intestine into the bloodstream.

    In order to design drugs that utilize CMT to cross the BBB, researchers modify their chemical structures so that they resemble nutrients that are transported across the BBB by specific SLCs. The prototypical drug that uses this strategy (which was developed long before mechanisms of CMT were known) is L-DOPA, the major current drug for Parkinson’s disease. L-DOPA is used to replace dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.

    Dopamine itself cannot cross the BBB. It can, however, be modified to produce L-DOPA, an amino acid that is recognized by the large neutral amino acid transporter. This SLC family member transports L-DOPA into the brain, where it is converted to dopamine by the enzyme aromatic amino acid decarboxylase. L-DOPA thus serves as a prodrug that crosses the BBB and is converted into the active agent in the brain. The structures of L-DOPA and dopamine are shown in Figure 1.

    XenoPort has been designing small molecule drugs that exploit CMT to enable improved absorption from the gut or transport across the BBB. The company refers to its products as Transported Prodrugs. These are prodrugs that target SLC nutrient transporters, either in the BBB or in the intestine. XenoPort’s main therapeutic focus is on CNS drugs, but it is also developing a drug for gastroesophageal reflux disease.

    All of Xenoport’s clinical-stage drugs target SLCs in the intestine. They are Transported Prodrugs that are derivatives of FDA-approved drugs and are modified to target an SLC. Once they are transported from the intestine into the bloodstream, they are converted into the active drug, analogous to the conversion of L-DOPA to dopamine.
    Xenoport’s research aimed at development of drugs that cross the BBB similarly involves the design of Transported Prodrugs that target SLCs in brain capillaries. Once they are transported through the BBB, they are converted into active drugs.


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