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Azetukalner

Azetukalner
Clinical data
Other namesEncukalner; XEN1101; XEN-1101
Routes of
administration		Oral[1]
Drug classKCNQ potassium channel opener
Identifiers
  • N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC23H29FN2O
Molar mass368.496 g·mol−1
3D model (JSmol)
  • CC1=CC(=CC(=C1NC(=O)CC(C)(C)C)C)N2CCC3=C(C2)C=CC(=C3)F
  • InChI=1S/C23H29FN2O/c1-15-10-20(11-16(2)22(15)25-21(27)13-23(3,4)5)26-9-8-17-12-19(24)7-6-18(17)14-26/h6-7,10-12H,8-9,13-14H2,1-5H3,(H,25,27)
  • Key:FJNPZKZPWVVSON-UHFFFAOYSA-N

Azetukalner, also known as encukalner and XEN1101, is an experimental small molecule anticonvulsant and selective Kv7.2/Kv7.3 potassium channel opener being investigated as a treatment for refractory focal onset seizures[2][3][4][5][6] and major depressive disorder.[6][1]

Mechanism of action

Azetukalner works by selectively opening the KCNQ2/3 (Kv7.2/Kv7.3) voltage-gated potassium channels via positive allosteric modulation. The opening of these voltage-gated potassium channels, which are critical regulators of neuronal excitability, leads to an increase in the flow of potassium ions out of neurons. The loss of positively charged potassium ions results in the inside of the neuron becoming negatively charged and hyperpolarized. This hyperpolarized resting state reduces the ability of the neuron to fire, thereby decreasing the likelihood of seizures.[3][4][6]

This mechanism of action shares similarities with the medication retigabine, which was withdrawn from the market in 2017 due to its link to skin pigmentation and retinitis pigmentosa.[2][3][6][7] Azetukalner has a different structure and does not appear to cause this effect or the development of the chromophoric phenazinium-type dimers that resulted in this side effect in retigabine.[2]

Chemistry

Analogues

Azetukalner is an analogue of flupirtine, retigabine (ezogabine), and pynegabine.

See also

References

  1. ^ a b "Xenon Pharmaceuticals". AdisInsight. 27 April 2026. Retrieved 31 May 2026.
  2. ^ a b c Pong AW, Ross J, Tyrlikova I, Giermek AJ, Kohli MP, Khan YA, Salgado RD, Klein P (March 2022). "Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials". Expert Opinion on Emerging Drugs. 27 (1): 75–90. doi:10.1080/14728214.2022.2059464. PMID 35341431. S2CID 247763576.
  3. ^ a b c Premoli I, Rossini PG, Goldberg PY, Posadas K, Green L, Yogo N, Pimstone S, Abela E, Beatch GN, Richardson MP (November 2019). "TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101". Annals of Clinical and Translational Neurology. 6 (11): 2164–2174. doi:10.1002/acn3.50896. PMC 6856596. PMID 31568714. XEN1101 is a novel positive allosteric modulator ("opener") of the potassium channel KCNQ2/3 (Kv7.2/7.3) currently being developed by Xenon Pharmaceuticals Inc. for the treatment of focal epilepsy. Potentiating the open state of KCNQ2/3 channels favors a hyperpolarized resting state. This mechanism has been clinically proven effective for focal onset seizures using the KCNQ2/3 opener, retigabine.
  4. ^ a b Ciccone I (10 October 2023). "Potassium Channel Opener XEN1101 Offers Simplicity and Strong Efficacy in Seizure Control". Neurology live. Retrieved 11 October 2023. XEN1101 (Xenon Pharmaceuticals), part of a class of chemicals called potassium-channel openers, is an investigational antiseizure medication in development for patients with focal epilepsy. This treatment is designed to avert seizures by boosting the flow of potassium out of nerves and stopping them from firing.
  5. ^ French JA, Porter RJ, Perucca E, Brodie MJ, Rogawski MA, Pimstone S, Aycardi E, Harden C, Qian J, Luzon Rosenblut C, Kenney C, Beatch GN (October 2023). "Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial". JAMA Neurology. 80 (11): 1145–1154. doi:10.1001/jamaneurol.2023.3542. PMC 10562989. PMID 37812429.
  6. ^ a b c d Costi S, Han MH, Murrough JW (March 2022). "The Potential of KCNQ Potassium Channel Openers as Novel Antidepressants". CNS Drugs. 36 (3): 207–216. doi:10.1007/s40263-021-00885-y. PMID 35258812. S2CID 247294637.
  7. ^ Hackethal V (15 June 2017). "Anticonvulsant Potiga Discontinued in June 2017". Neurology live. Retrieved 11 October 2023.

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