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Novel, Broad-Spectrum Anticonvulsants Containing a Sulfamide Group: Pharmacological Properties of (S)‑N‑[(6-Chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112)

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journal contribution
posted on 27.11.2013, 00:00 by David F. McComsey, Virginia L. Smith-Swintosky, Michael H. Parker, Douglas E. Brenneman, Ewa Malatynska, H. Steve White, Brian D. Klein, Karen S. Wilcox, Michael E. Milewski, Mark Herb, Michael F. A. Finley, Yi Liu, Mary Lou Lubin, Ning Qin, Allen B. Reitz, Bruce E. Maryanoff
Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such “neurostabilizers” have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (49, 10ai, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na+ channels and N-type Ca2+ channels and was effective as a K+ channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.