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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.
- 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.
- Subjects :
- Amides metabolism
Amides pharmacokinetics
Animals
Anticonvulsants metabolism
Anticonvulsants pharmacokinetics
Carbonic Anhydrase II antagonists & inhibitors
Cell Line
Clinical Trials as Topic
Drug Evaluation, Preclinical
Female
Humans
Male
Mice
Rats
Sulfonamides metabolism
Sulfonamides pharmacokinetics
Thiophenes metabolism
Thiophenes pharmacokinetics
Amides chemistry
Amides pharmacology
Anticonvulsants chemistry
Anticonvulsants pharmacology
Sulfonamides chemistry
Sulfonamides pharmacology
Thiophenes chemistry
Thiophenes pharmacology
Subjects
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