Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 23, Pages 7528-7536Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm801432r
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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.
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