title: Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies.
abstract: 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 (IC(50) = 110 microM). 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 Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.
authors.affiliation: Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Parker
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Smith-Swintosky
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Yifang
authors.initials: Y
authors.lastname: Huang
authors.forename: Douglas
authors.initials: D
authors.lastname: Brenneman
authors.forename: Brian
authors.initials: B
authors.lastname: Klein
authors.forename: Ewa
authors.initials: E
authors.lastname: Malatynska
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
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: Robert
authors.initials: R
authors.lastname: Iannucci
authors.forename: Laurent
authors.initials: L
authors.lastname: Leclercq
authors.forename: Filip
authors.initials: F
authors.lastname: Cuyckens
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D002460:Cell Line; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000577:Amides; D000927:Anticonvulsants; D013449:Sulfonamides; D013876:Thiophenes; D024402:Carbonic Anhydrase II; C545991:N-((benzo(b)thien-3-yl)methyl)sulfamide