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

doi:10.1016/j.bmcl.2015.04.074

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 21, 1 November 2015, Pages 4941-4944

https://doi.org/10.1016/j.bmcl.2015.04.074 Get rights and content

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.

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Acknowledgements

The authors wish to acknowledge the assistance of Kari Fonseca, Rich Zanzalari, Jotham Coe, and Steve Jenkinson.

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Neuronal voltage-gated potassium channels, K_V7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule K_V7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. K_V7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual K_V7 isoforms was investigated in human detrusor tissue using a panel of K_V7 openers with distinct activity profiles among K_V7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric K_V7.4 did not reduce detrusor contraction. This may suggest that the homomeric K_V7.4 channel plays a less significant role in bladder contraction and further investigation is needed.
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Discovery of a novel Kv7 channel opener as a treatment for epilepsy

Abstract

Graphical abstract

Section snippets

Acknowledgements

Curr. Opin. Pharmacol.

Eur. J. Pharmacol.

J. Org. Chem.

Br. J. Clin. Pharmacol.

Drug Metabol. Disposition

J. Physiol.

Brain

J. Physiol.

Mol. Pharmacol.

Seizure

Eur. J. Pharmacol.