IDOR-1104-0086, a novel Kv7 channel activator with antiseizure effects in rodents.

A neuronal, phenotypic in vitro screen at Idorsia identified IDOR-1104-0086 as a small molecule with antiseizure effects and drug-like properties. Target deconvolution revealed its mechanism as activating voltage-gated potassium (Kv7) channels, which stabilize the resting membrane potential and modulate cellular excitability. In the current study, we further investigated IDOR-1104-0086's potency and selectivity profile on Kv7.1-7.5 isoforms and compared it to the known Kv7 channel opener and antiseizure medication retigabine. We studied its effects in the amygdala-kindling and 6 Hz rodent models of focal-onset seizures, the maximal electroshock threshold test of generalized convulsive seizures in mice, and a model of absence-like epilepsy in rats featuring non-convulsive generalized seizures. IDOR-1104-0086 demonstrated greater potency than retigabine on various Kv7 isoforms, including the brain-specific Kv7.2/3 and Kv7.3/5 heterotetramers, and was inactive on the peripheral Kv7.1 isoform expressed on cardiac myocytes. It reduced focal-onset and generalized convulsive seizures in a dose-dependent manner in the employed models. However, it aggravated non-convulsive seizures similarly to retigabine. Unbound IDOR-1104-0086 plasma concentrations that were well tolerated and efficacious in vivo caused a therapeutically relevant shift of the Kv7.2/3 current activation in whole-cell patch-clamp electrophysiology recordings, consistent with retigabine's effects. IDOR-1104-0086 is a potent activator of Kv7.2/3 channels that reduces focal-onset and generalized convulsive seizures in rodent models while being well tolerated. Its efficacious Kv7 channel activation properties make it a promising drug candidate for the treatment of drug-resistant epilepsy with focal-onset or generalized convulsive seizures.