Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies.
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.
Parker
Michael H
MH
Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
Smith-Swintosky
Virginia L
VL
McComsey
David F
DF
Huang
Yifang
Y
Brenneman
Douglas
D
Klein
Brian
B
Malatynska
Ewa
E
White
H Steve
HS
Milewski
Michael E
ME
Herb
Mark
M
Finley
Michael F A
MF
Liu
Yi
Y
Lubin
Mary Lou
ML
Qin
Ning
N
Iannucci
Robert
R
Leclercq
Laurent
L
Cuyckens
Filip
F
Reitz
Allen B
AB
Maryanoff
Bruce E
BE
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*
D000577:Amides; D000927:Anticonvulsants; D013449:Sulfonamides; D013876:Thiophenes; D024402:Carbonic Anhydrase II; C545991:N-((benzo(b)thien-3-yl)methyl)sulfamide