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NEWS & EVENTS
Superior Potency: Some molecules demonstrated an EC50 of 50 nM on Kv7.2/7.3 in a patch clamp, surpassing current Kv7 modulators, such as XEN1101 and BHV7000.
Enhanced Efficacy: Molecules exhibit a >200-fold improvement in Kv7.2 channel opening, with a 25% increase in Emax over ezogabine.
In Vivo Validation: In rodent models, molecules showed full protection against maximal electroshock-induced seizures (MES) at doses as low as 3 mg/kg in rats and 7 mg/kg in mice, with ED50 values > 0.3 mg/kg in rat, achieving superior efficacy compared to drugs in clinical development.
PK/PD Relationship: Plasma levels > 200 nM and brain levels > 40 nM led to > 75% of the mice and rats tested protected from the MES induced convulsion.
Translational Potential: Pharmacokinetic allometric 2-species scaling suggests a 5 mg human dose to be above the 200 nM threshold for 24 h after a single dose, exhibit a half-life of 31 h and allow for self-titration.
Poster Title: “New Kv7 Channel Opener Chemistry for the Treatment of Seizures”
Session: Poster Session 1.396, December 8, 2024
Authors: Christopher Crean, Stevie Pope, Polina Danshina, Matthew Rich, David Fischler, Sarah Thrasher, and Angela Dixon
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