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From Retigabine to Azetukalner: Reviving Voltage-Gated Potassium Channels for Epilepsy Therapy
Pascal Rosendahl1, Lukas Schulig1, Andreas Link1
1Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany.
Archiv Der Pharmazie
|July 3, 2026
Summary
Azetukalner (XEN1101), a novel modulator of KV7.2/3 potassium channels, offers improved properties over earlier drugs like retigabine. It addresses toxicity concerns and shows promise for treating KV7.2/3 channelopathies, including epilepsy.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- KV7.2/3 potassium channels are targets for epilepsy and pain, but flupirtine and retigabine (ezogabine) were withdrawn due to toxicity.
- Toxicity of flupirtine and retigabine is linked to an oxidation-sensitive metabophore, not inherent to KV7.2/3 channel modulation.
- KV7.2/3 channelopathies, particularly epilepsy, represent a therapeutic gap necessitating new modulator development.
Purpose of the Study:
- To introduce azetukalner (XEN1101), a novel KV7.2/3 channel modulator designed to overcome the limitations of previous agents.
- To detail the retrometabolic drug design strategy employed to create azetukalner, focusing on remodeling toxicophore elements.
- To review the synthesis, physicochemical characteristics, and clinical findings of azetukalner.
Main Methods:
- Retrometabolic drug design was used to remodel the carbamate and central ring structures of retigabine.
- Azetukalner was synthesized and its metabolic stability, potency, and blood-brain barrier penetration were evaluated.
- Physicochemical properties and clinical trial results of azetukalner were compiled and analyzed.
Main Results:
- Azetukalner (XEN1101) demonstrates improved metabolic stability compared to retigabine.
- The novel compound exhibits enhanced potency and superior blood-brain barrier penetration.
- Early clinical data suggest a favorable profile for azetukalner in relevant indications.
Conclusions:
- Azetukalner represents a promising next-generation KV7.2/3 channel modulator, addressing the toxicity issues of its predecessors.
- Its improved pharmacokinetic and pharmacodynamic properties make it a strong candidate for treating KV7.2/3 channelopathies, including epilepsy.
- Further clinical investigation of azetukalner is warranted to fully establish its therapeutic potential.
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