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Clemizole

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Clemizole
BERJAYA
Clinical data
Trade namesAllercur, Histacur
Other namesEPX-100
ATC code
  • None
Identifiers
  • 1-[(4-Chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.006.486 Edit this at Wikidata
Chemical and physical data
FormulaC19H20ClN3
Molar mass325.84 g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1)Cn3c(nc2ccccc23)CN4CCCC4
  • InChI=1S/C19H20ClN3/c20-16-9-7-15(8-10-16)13-23-18-6-2-1-5-17(18)21-19(23)14-22-11-3-4-12-22/h1-2,5-10H,3-4,11-14H2
  • Key:CJXAEXPPLWQRFR-UHFFFAOYSA-N

Clemizole, sold under the brand names Allercur and Histacur, is a histamine H1 receptor antagonist of the benzimidazole group described as an antihistamine, antipruritic, and sedative which is no longer marketed.[1][2][3][4] It is a first-generation antihistamine.[5]

It is also a serotonin receptor agonist and is being studied for the potential treatment of Dravet syndrome, Lennox–Gastaut syndrome, and epilepsy under the development code name EPX-100.[6][4][7] The drug is said to act specifically as a serotonin 5-HT2 receptor agonist,[8][9] with prominent affinity for the serotonin 5-HT2A and 5-HT2B receptors having been reported.[5][4] On the other hand, it showed markedly lower affinity for the serotonin 5-HT2C receptor.[4] Clemizole also showed affinity for several other receptors.[4]

The drug was first described in the scientific literature by 1952.[1] Its serotonin receptor agonist and anticonvulsant properties were discovered in 2017.[6][4]

Chemistry

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Synthesis

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Benzimidazoles substituted with an alkylamine at position 2 have a venerable history as H1 antihistaminic agents. The standard starting material for many benzimidazoles consists of phenylenediamine, or its derivatives.

BERJAYA
Clemizole synthesis:[10][11][12]

Reaction of that compound with chloroacetic acid can be rationalized by invoking initial formation of the chloromethyl amide. Imide formation with the remaining free amino group closes the ring to afford 2-chloromethyl benzimidazole (3). Displacement of halogen with pyrrolidine affords the alkylation product. The proton on the fused imidazole nitrogen is then removed by reaction with sodium hydride. Treatment of the resulting anion with α,4-dichlorotoluene gives the H1 antihistaminic agent clemizole (5).

See also

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References

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  1. 1 2 Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 288. ISBN 978-1-4757-2085-3. Retrieved 29 October 2024.
  2. ↑ Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 291. ISBN 978-3-88763-101-7. Retrieved 29 October 2024.
  3. ↑ Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 78. ISBN 978-94-011-4439-1. Retrieved 29 October 2024.
  4. 1 2 3 4 5 6 Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC (March 2017). "Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome". Brain. 140 (3): 669–683. doi:10.1093/brain/aww342. PMC 6075536. PMID 28073790.
  5. 1 2 Bagchi VA, Ziobro J, Isom LL (2025). "Dravet syndrome therapeutics: where are we, what works, and what's next?". Expert Opin Pharmacother. 26 (14–15): 1549–1564. doi:10.1080/14656566.2025.2576608. PMID 41114441. A first-generation antihistamine from the 1950s, clemizole fell out of use with the advent of newer antihistaminergic drugs [77]. Unexpectedly, it resurfaced as a promising anticonvulsant in a 2013 high-throughput, phenotype-based drug screen [78]. The Baraban group employed a zebrafish model harboring Scn1a haploinsufficiency, displaying seizure-like behaviors and electrographic abnormalities, to screen over 2,300 small molecules. Clemizole emerged as a potent seizure suppressor, acting primarily via serotonergic receptor modulation, notably at 5-HT2A and 5-HT2B subtypes [68].
  6. 1 2 Sills GJ (2023). "Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies". Ther Adv Neurol Disord. 16 17562864231191000. doi:10.1177/17562864231191000. PMC 10467199. PMID 37655228.
  7. ↑ "Clemizole - Epygenix Therapeutics/University of California at San Francisco". AdisInsight. 9 October 2024. Retrieved 29 October 2024.
  8. ↑ Pasculli L (27 March 2026). "EPX-100 Shows Promising Seizure Reduction in Ongoing Open-Label Extension". NeurologyLive. Retrieved 27 March 2026.
  9. ↑ Amit Ray (8 December 2025). "EPX-100 as Adjunctive Therapy in Patients With Dravet Syndrome: Preliminary Results From the Open-Label Extension Phase of the ARGUS Study". Retrieved 27 March 2026.
  10. ↑ Jerchel D, Fischer H, Kracht M (1952). "Zur Darstellung der Benzimidazole". Justus Liebigs Annalen der Chemie. 575 (2): 162–173. doi:10.1002/jlac.19525750204.
  11. ↑ GB 703272, Schenck M, Heinz W, issued 1954, assigned to Schering AG
  12. ↑ US 2689853, Schenck M, Heinz W, issued 1954, assigned to Schering AG
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