Abstracts

Rationale: Epilepsy is a chronic neurological disorder characterized by spontaneous, recurrent seizures that affects up to 2% of the world's population. Seizures can occur due to malfunctioning ion channels, increased excitatory neurotransmission activity or decreased inhibitory neurotransmission activity. Approximately 25-30% of patients with epilepsy fail to experience adequate control of their seizures despite the optimal use of available antiepileptic drugs (AEDs), or they have control of their seizures but experience acute adverse effects. Discovery of novel agents that can correct or prevent the ionic disruption with improve side effect profiles is a key milestone in the battle against epilepsy. The primary objective for this research is to develop novel aryl enaminone analogs that have the potential to be more effective, selective, and safer anticonvulsant agents. Methods: The 6-membered cyclic diketones of the mono-methyl, dimethyl and unsubstituted analogs underwent an amination reaction to yield the desired enaminone intermediate(s). Subsequently, selective enaminone intermediates underwent base-catalyzed sulfonylation or acylation reactions to generate the target compounds. Each compound was confirmed by melting point, proton Nuclear Magnetic Resonance (NMR), and elemental analyses. Results: Our initial evaluation of a library of sulfonamide enaminones gave encouraging data, as 19 of the 30 compounds showed activity in the Maximal Electroshock Seizure (MES) or the 6-Hertz psychomotor seizure animal models. To continue with our extensive SAR studies, seven novel aryl enaminones were successfully synthesized and six were submitted for pharmacological testing as anticonvulsants to the National Institute of Neurological Disorders and Stroke, NIH. Four compounds were found to be active in the mouse MES model at 100mg/kg and one analog in the subcutaneous pentylenetetrazol (scPTZ) model at 100mg/kg. THA 40 showed promising activity in the rat MES model at 30 mg/kg at 0.5h. While THA 36 is the one analog thus far that has shown 6 Hz psychomotor activity at 100 mg/kg during time intervals 0.25, 0.5, and 1.0 hours in mice. The active compounds had little to no neurotoxicity. Conclusions: To date we have a total library of 37 novel aryl enaminones. Six novel enaminone analogs were recently evaluated and all six compounds showed good to moderate protection in the mouse. All tested compounds are undergoing further screening in the 6-Hz seizure model and neuroprotection assays at NINDS.