From Retigabine to Azetukalner: Reviving Voltage-Gated Potassium Channels for Epilepsy Therapy

Heterotetrameric K_V7.2/3 potassium channels were retrospectively identified as the target of the analgesic flupirtine and the antiepileptic retigabine (ezogabine). Clinical utility of these agents ended after decades or 6 years, respectively, before their full scope was explored. Market withdrawals in 2017 and 2018 hampered research in other medical fields and left a gap for researchers using these compounds off-label in experimental indications and for patients with K_V7.2/3 malfunctions. Failure of these drugs might be regarded as a reason to abandon this class of compounds, due to the notion that toxicity might be a class effect and to competitive markets. Yet, evidence accumulated that the toxicity of both compounds is not an inherent property of modulators of K_V7.2/3 channels, but rather the result of an oxidation-sensitive metabophore/toxicophore. Second, epilepsy associated with K_V7.2/3 channelopathies might rationally be addressed best with modulators of this validated drug target. Employing retrometabolic drug design to remodel the enzyme-labile carbamate structure and the central highly substituted ring, azetukalner (formerly encukalner, XEN1101) emerged from the unlucky forerunners. This structural analog of retigabine exhibits improved metabolic stability, increased potency, and enhanced blood-brain barrier penetration compared with its predecessor. This review details the synthesis, physicochemical properties, and clinical results of azetukalner.