4区 · 医学
Article
作者: Rogers, Bruce N ; Reese, Matthew R ; Whisman, Tammy L ; Rong, SuoBao ; Moine, Ludivine ; Butler, Christopher R ; Wright, Ann S ; Schuyten, Katherine ; Rong, Haojing ; Tse, Karen ; Drozda, Susan E ; Lowe, John A ; Stolyar, Polina ; Duplantier, Allen J ; Weber, Mark L ; Arora, Gaurav ; Baker, Karen ; Snow, Sheri L ; Chenard, Lois ; Serpa, Kevin A ; Zhang, Lei ; Boscoe, Brian P ; DeNinno, Shari L ; Claffey, Michelle M ; Davoren, Jennifer E ; Clark, Alan J ; Mather, Robert J
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.