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)

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. W...

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Published in:Journal of medicinal chemistry 2013-11, Vol.56 (22), p.9019-9030
Main Authors: McComsey, David F, Smith-Swintosky, Virginia L, Parker, Michael H, Brenneman, Douglas E, Malatynska, Ewa, White, H. Steve, Klein, Brian D, Wilcox, Karen S, Milewski, Michael E, Herb, Mark, Finley, Michael F. A, Liu, Yi, Lubin, Mary Lou, Qin, Ning, Reitz, Allen B, Maryanoff, Bruce E
Format: Article
Language:English
Subjects:
Absorption
Amides - chemistry
Amides - pharmacokinetics
Amides - pharmacology
Amides - therapeutic use
Animals
Anticonvulsants - chemistry
Anticonvulsants - pharmacokinetics
Anticonvulsants - pharmacology
Anticonvulsants - therapeutic use
Dioxanes - chemistry
Dioxanes - pharmacokinetics
Dioxanes - pharmacology
Dioxanes - therapeutic use
Dogs
Drug Evaluation, Preclinical
Drug Resistance
Epilepsy - drug therapy
Female
Humans
Male
Mice
Rats
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
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Summary: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 (4–9, 10a–i, 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm400894u