Unmet NeedLennox-Gastaut Syndrome (LGS) is rare and severe form of childhood-onset epilepsy associated with various types of seizures and cognitive dysfunction that persist into adulthood; yet, to date, LGS management is challenged by the lack of reliable diagnostic tests and potentially grave side-effects of available therapeutics. Rufinamide is a promising new compound with broad anti-epileptic activity; however, its mode of action remains speculative, thereby hampering the wide-spread use of the drug. Hence, this invention discovered that rufinamide exerts its function primarily via modulating the activity of a particular sodium channel isoform (hNav), and further identified strongly anti-epileptic structural rufinamide analogs, useful for the efficient treatment of LGS, related epileptic disorders, and and diseases such as cognitive impairment without seizures, migraine, autism, and post-traumatic stress disorder. Advantages include:
- Unraveling of a hNav isoform as the target of rufinamide enables development of additional effective drugs
- Structural derivative compounds of rufinamide for an efficacious therapy of epileptic diseases and seizures
- Significantly reduced seizure occurrence and severity in 3 animal models widely applicable for epilepsy disorders
Technology Overview
Johns Hopkins researchers have designed structural derivatives of the newly discovered anti-epileptic drug rufinamide that exhibit strongly enhanced inhibition of a voltage-gated sodium channel, thus presenting valuable new therapeutics for epileptic diseases and seizure disorders. Inventors explored the mode of action of rufinamide, a recently identified anti-epileptic drug with a unique hydrophobic triazole-derived molecular structure. Of the nine sodium channel isoforms identified in humans, four are predominantly expressed in the central nervous system. Interestingly, clinically relevant rufinamide concentrations only slightly alter recovery from fast inactivation of these four neuronal isoforms; yet, the drug dramatically inhibits activation of one particular isoform. Importantly, structure-activity relationship studies identified rufinamide derivatives chemically modified at particular positions on the triazole pharmacophore with notably enhanced efficacy. Therefore, this technology provides a panel of biologically active rufinamide derivatives that can be exploited to obtain high efficacy of drug-induced inhibition of activation of a specific sodium channel isoform, valuable as novel therapeutics for LGS and related disorders.
Stage of Development
Pre-Clinical
