Discovery of a novel Kv7 channel opener as a treatment for epilepsy

  • Bioorg Med Chem Lett. 2015 Nov 1;25(21):4941-4944. doi: 10.1016/j.bmcl.2015.04.074.
Jennifer E Davoren  1 ,  Michelle M Claffey  2 ,  Sheri L Snow  2 ,  Matthew R Reese  2 ,  Gaurav Arora  2 ,  Christopher R Butler  1 ,  Brian P Boscoe  2 ,  Lois Chenard  2 ,  Shari L DeNinno  2 ,  Susan E Drozda  2 ,  Allen J Duplantier  2 ,  Ludivine Moine  2 ,  Bruce N Rogers  2 ,  SuoBao Rong  2 ,  Katherine Schuyten  2 ,  Ann S Wright  2 ,  Lei Zhang  1 ,  Kevin A Serpa  2 ,  Mark L Weber  2 ,  Polina Stolyar  1 ,  Tammy L Whisman  2 ,  Karen Baker  2 ,  Karen Tse  3 ,  Alan J Clark  2 ,  Haojing Rong  2 ,  Robert J Mather  4 ,  John A Lowe 3rd  5
Affiliations
  • 1. Pfizer, 610 Main Street, Cambridge, MA, United States.
  • 2. Pfizer, Eastern Point Road, Groton, CT, United States.
  • 3. Pfizer, Drug Safety Research & Development, Sandwich, United Kingdom.
  • 4. AstraZeneca Neuroscience iMED, 141 Portland St., Cambridge, MA, United States.
  • 5. JL3Pharma LLC, 28 Cove Side Lane, Stonington, CT, United States. Electronic address: [email protected].
PMID: 25987375 DOI: 10.1016/j.bmcl.2015.04.074
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.

Keywords
Amygdala-kindled seizure; Dimethoxypyrimidine; KCNQ; Kv7 channel opener; Maximal electroshock; PF-05020182; Pentylenetetrazole-induced seizure.
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