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Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies.

Authors :
Parker MH
Smith-Swintosky VL
McComsey DF
Huang Y
Brenneman D
Klein B
Malatynska E
White HS
Milewski ME
Herb M
Finley MF
Liu Y
Lubin ML
Qin N
Iannucci R
Leclercq L
Cuyckens F
Reitz AB
Maryanoff BE
Source :
Journal of medicinal chemistry [J Med Chem] 2009 Dec 10; Vol. 52 (23), pp. 7528-36.
Publication Year :
2009

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
52
Issue :
23
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
19388676
Full Text :
https://doi.org/10.1021/jm801432r