Novel, Broad-Spectrum Anticonvulsants Containing a Sulfamide Group: Advancement of N-((Benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into Human Clinical Studies

In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC50 = 110 mu M). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na+ channels and N-type Ca2+ channels but was not effective as a K+ channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.