Characterization of BHV-7000: A Novel Kv7.2/7.3 Activator for the Treatment of Seizures
Kelly Picchione1, Lynn Resnick1, Michael Bozik1, Steven Dworetzky1
1Biohaven Pharmaceuticals, Inc
Objective:
Assess in vitro activity and in vivo efficacy, safety, and tolerability of BHV-7000.
Background:
Kv7 channels are voltage-gated potassium channels encoded by KCNQ genes that exert physiological control over excitable cells. The Kv7.2/7.3 channel subtype generates the M-current in the central nervous system that represents a clinically validated drug target for treating seizures. Positive modulation of M-current facilitates normalizing the excitation/inhibition imbalance that occurs in epilepsy patients.
Design/Methods:
BHV-7000 was rationally designed from a novel Kv7 pharmacophore platform. Fluorescent and electrophysiological assays were employed to discover and characterize lead compounds. Antiseizure efficacy was evaluated in rats in the maximal electroshock seizure (MES) model; tolerability was assessed by neurological score (NS) and rotarod assays. Cells transiently transfected with mutant (W236L) or wildtype KCNQ2 were used to characterize BHV-7000 activity at Kv7.2 channels.
Results:
BHV-7000 activates the Kv7.2/7.3 channel with an EC50 of 0.6 μM. BHV-7000 slowed deactivation kinetics and shifted the half-maximal activation potential. In rat primary cortical neuron cultures, BHV-7000 produced a concentration dependent hyperpolarization of the resting membrane potential. BHV-7000 requires the W236 amino acid for activity on the Kv7.2 channel. BHV-7000 demonstrated little to no effect against the human α1β3ɣ2 GABA receptor at 10 μM and no significant activity against cardiac ion channels. In the MES model, BHV-7000 provides protection against seizures with a brain EC50 of 0.12 μM and TD50 >20 mg/kg, measured by NS, a sensitive measure of tolerability. The rotarod assay demonstrated no motor effects across all doses.
Conclusions:
BHV-7000 is a novel activator of Kv7.2/7.3 potassium channels in development for the treatment of epilepsy. BHV-7000 displays potent antiseizure activity in the rat MES model with no overt neurobehavioral or motor effects, and thus represents a promising next generation ASM for clinical development.