Referenced in: none

Automatically associated channels: Kv7.2

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

Authors: Jennifer E Davoren, Michelle M Claffey, Sheri L Snow, Matthew R Reese, Gaurav Arora, Christopher R Butler, Brian P Boscoe, Lois Chenard, Shari L DeNinno, Susan E Drozda, Allen J Duplantier, Ludivine Moine, Bruce N Rogers, SuoBao Rong, Katherine Schuyten, Ann S Wright, Lei Zhang, Kevin A Serpa, Mark L Weber, Polina Stolyar, Tammy L Whisman, Karen Baker, Karen Tse, Alan J Clark, Haojing Rong, Robert J Mather, John A Lowe

Journal, date & volume: Bioorg. Med. Chem. Lett., 2015 Nov 1 , 25, 4941-4

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25987375

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.