Document Report Card

ID: ALA1153762

Journal: J Med Chem

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.

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.

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.

CiteXplore: 19388676

DOI: 10.1021/jm801432r