title: Discovery of a novel Kv7 channel opener as a treatment for epilepsy.
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.
authors.affiliation: Pfizer, 610 Main Street, Cambridge, MA, United States.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Davoren
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Claffey
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Snow
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reese
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Arora
authors.affiliation: Pfizer, 610 Main Street, Cambridge, MA, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Butler
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Boscoe
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Lois
authors.initials: L
authors.lastname: Chenard
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Shari L
authors.initials: SL
authors.lastname: DeNinno
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Drozda
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Duplantier
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Moine
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Rogers
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: SuoBao
authors.initials: S
authors.lastname: Rong
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Schuyten
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Ann S
authors.initials: AS
authors.lastname: Wright
authors.affiliation: Pfizer, 610 Main Street, Cambridge, MA, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Serpa
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Weber
authors.affiliation: Pfizer, 610 Main Street, Cambridge, MA, United States.
authors.forename: Polina
authors.initials: P
authors.lastname: Stolyar
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Whisman
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Baker
authors.affiliation: Pfizer, Drug Safety Research & Development, Sandwich, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Tse
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Clark
authors.affiliation: Pfizer, Eastern Point Road, Groton, CT, United States.
authors.forename: Haojing
authors.initials: H
authors.lastname: Rong
authors.affiliation: AstraZeneca Neuroscience iMED, 141 Portland St., Cambridge, MA, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mather
authors.affiliation: JL3Pharma LLC, 28 Cove Side Lane, Stonington, CT, United States. Electronic address: jal3rd@gmail.com.
authors.forename: John A
authors.initials: JA
authors.lastname: Lowe
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051658:KCNQ2 Potassium Channel / Q000819:agonists / Q000378:metabolism*; D008861:Microsomes / Q000187:drug effects; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D051658:KCNQ2 Potassium Channel; C000608352:PF-05020182; D010880:Piperidines; D011743:Pyrimidines
keywords: Amygdala-kindled seizure; Dimethoxypyrimidine; KCNQ; Kv7 channel opener; Maximal electroshock; PF-05020182; Pentylenetetrazole-induced seizure