Clemizole

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]

Clemizole

Clinical data
Trade names	Allercur, Histacur
Other names	EPX-100
ATC code	None
Identifiers
IUPAC name 1-[(4-Chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole
CAS Number	442-52-4
PubChem CID	2782
ChemSpider	2680
UNII	T97CB3796L
KEGG	D01705
ChEBI	CHEBI:52140
ChEMBL	ChEMBL1407943
NIAID ChemDB	033090
CompTox Dashboard (EPA)	DTXSID0046939
ECHA InfoCard	100.006.486
Chemical and physical data
Formula	C19H20ClN3
Molar mass	325.84 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc1ccc(cc1)Cn3c(nc2ccccc23)CN4CCCC4
InChI 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

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.^[5][4][6]

The drug was first described in the scientific literature by 1952.^[1] Its serotonin receptor agonist and anticonvulsant properties were discovered in 2017.^[5][4]

Synthesis

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.

Clemizole synthesis:^[7][8][9]

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

• Chlormidazole

References

1. 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. 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. 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. 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.
6. "Clemizole - Epygenix Therapeutics/University of California at San Fransisco". AdisInsight. 9 October 2024. Retrieved 29 October 2024.
7. 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.
8. GB 703272, Schenck M, Heinz W, issued 1954, assigned to Schering AG
9. US 2689853, Schenck M, Heinz W, issued 1954, assigned to Schering AG