A Novel ER Beta Ligand Prodrug to Treat MS and Other Neurodegenerative Diseases

Researchers from the Department of Neurology and the Department of Chemistry and Biochemistry at UCLA have developed a novel ERβ ligand prodrug that is structurally designed to more easily cross the blood-brain barrier for treatment of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and demyelination of the central nervous system. Current MS treatments have immunomodulatory effects and reduce relapse rates in MS patients, but have only modest effects on disability progression. Recent studies have shown that treatment with estrogens or estrogen receptor (ER) specific-ligands in the mouse model for MS (experimental autoimmune encephalomyelitis (EAE)) are neuroprotective and could ameliorate the effects of MS. Specifically, ERβ ligand-treated animals exhibited preserved axons and myelin compared with vehicle-treated animals. Unfortunately, the concentration of diarylpropionitrile (DPN), the generic ERβ ligand, needed to ameliorate EAE in mice is relatively high. The required dosage results in high off-target effects and is therefore unsafe for clinical use. The need for such large amounts of this drug to treat MS is speculated to be a result of low passage through the blood-brain barrier. In order for ERβ ligands to become clinically useful in the treatment of MS, they must have increased blood-brain barrier permeability and be effective at lower concentrations.

Researchers at UCLA from the Department of Neurology and the Department of Chemistry and Biochemistry have developed a novel ERβ ligand prodrug that crosses the blood-brain barrier more effectively than DPN. Dosing with this ERβ ligand prodrug results in lower peripheral blood concentration of ER ligand, thereby lessening the exposure of breast, uterus and other off-target tissues to the active molecule. After the drug moves into the central nervous system, it is cleaved and becomes active, resulting in higher brain and spinal cord concentrations over the hours that follow. 

In vivo testing on mouse model of MS (EAE) shows that initial concentrations of active drug were lower in the blood but increased in the central nervous system over multiple hours. The novel ERβ ligand prodrug was also more effective at treating EAE in mice.