Discovery of a novel Kv7 channel opener as a treatment for epilepsy. Issue 21 (1st November 2015)

• Record Type: Journal Article
• Authors: Davoren, Jennifer E.; Claffey, Michelle M.; Snow, Sheri L.; Reese, Matthew R.; Arora, Gaurav; Butler, Christopher R.; Boscoe, Brian P.; Chenard, Lois; DeNinno, Shari L.; Drozda, Susan E.; Duplantier, Allen J.; Moine, Ludivine; Rogers, Bruce N.; Rong, SuoBao; Schuyten, Katherine; Wright, Ann S.; Zhang, Lei; Serpa, Kevin A.; Weber, Mark L.; Stolyar, Polina; Whisman, Tammy L.; Baker, Karen; Tse, Karen; Clark, Alan J.; Rong, Haojing; Mather, Robert J.; Lowe, John A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 21(2015)
• Page Start: 4941
• Page End: 4944
• Publication Date: 2015-11-01
• Subjects: Kv7 channel opener -- KCNQ -- PF-05020182 -- Dimethoxypyrimidine -- Maximal electroshock -- Pentylenetetrazole-induced seizure -- Amygdala-kindled seizure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.04.074
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.