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Basic Information

ID: ALA3621090

Journal: Bioorg Med Chem Lett

Title: Discovery of a novel Kv7 channel opener as a treatment for epilepsy.

Authors: Davoren JE, Claffey MM, Snow SL, Reese MR, Arora G, Butler CR, Boscoe BP, Chenard L, DeNinno SL, Drozda SE, Duplantier AJ, Moine L, Rogers BN, Rong S, Schuyten K, Wright AS, Zhang L, Serpa KA, Weber ML, Stolyar P, Whisman TL, Baker K, Tse K, Clark AJ, Rong H, Mather RJ, Lowe JA.

Abstract: Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.

CiteXplore: 25987375

DOI: 10.1016/j.bmcl.2015.04.074