The epilepsies are a family of neurological disorders characterized by seizures which are transient, recurrent perturbations of normal brain function. As a chronic condition, epilepsy affects about 1 percent of the population in the United States. While anti-epileptic drug (AED) treatment is the standard therapy for epilepsy, one third of all patients remain unresponsive to currently available medications. A growing body of research indicates that controlling seizure activity is an important physiological function for somatostatin in the CNS. Therefore, centrally active somatostatin analogs have potential to be novel, effective AEDs with a well defined molecular mechanism of action. A new structural class of potent non-peptide somatostatin mimetics with demonstrated CNS activity provides the starting point of the plan. This class of compounds will be optimized for in vitro potency and lipophilicity. Potential CNS drugs selected based on these in vitro parameters will be screened in vivo for efficacy in the acute seizure, rat kindling model of epilepsy. The rat chronic limbic epilepsy model will be used (largely in Phase II) to screen for compounds that are also active against spontaneous seizures and therefore have the greatest potential for demonstrating clinical efficacy in man.
