title: 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).
abstract: 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 Ca(2+) 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.
authors.affiliation: Research & Development, Janssen Pharmaceutical Companies of Johnson & Johnson , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Smith-Swintosky
authors.forename: Michael H
authors.initials: MH
authors.lastname: Parker
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Brenneman
authors.forename: Ewa
authors.initials: E
authors.lastname: Malatynska
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.forename: Brian D
authors.initials: BD
authors.lastname: Klein
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
authors.forename: Michael E
authors.initials: ME
authors.lastname: Milewski
authors.forename: Mark
authors.initials: M
authors.lastname: Herb
authors.forename: Michael F A
authors.initials: MF
authors.lastname: Finley
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Lubin
authors.forename: Ning
authors.initials: N
authors.lastname: Qin
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000042:Absorption; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004146:Dioxanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000577:Amides; D000927:Anticonvulsants; D004146:Dioxanes; C585982:N-((6-chloro-2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)sulfamide; D013449:Sulfonamides