Chemistry:Astemizole
Astemizole (marketed under the brand name Hismanal, developmental code R43512) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It was withdrawn from the market globally in 1999 because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias due to hERG channel blockade).[1][2]
Pharmacology
Astemizole is a histamine H1-receptor antagonist. It has anticholinergic and antipruritic effects.
Astemizole is rapidly absorbed from the gastrointestinal tract and competitively binds to histamine H1 receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine).
Despite some earlier reports that astemizole does not cross the blood–brain barrier, several studies[3][4] have shown high permeability and high binding to protein folds associated with Alzheimer's.
Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[5]
Astemizole has been researched as a treatment for Creutzfeldt-Jakob Disease (CJD).[6]
Like many carbendazim-derived benzimidazoles, it has been reported to interact with tubulin and inhibit its polymerization.[7]
Toxicity
Astemizole has an oral LD50 of approximately 2052 mg/kg (in mice).
References
- ↑ "Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole". Journal of Cardiovascular Electrophysiology 10 (6): 836–843. June 1999. doi:10.1111/j.1540-8167.1999.tb00264.x. PMID 10376921.
- ↑ "Withdrawn medicines included in the essential medicines lists of 136 countries". PLOS ONE 14 (12). 2019. doi:10.1371/journal.pone.0225429. PMID 31791048. Bibcode: 2019PLoSO..1425429C.
- ↑ "Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer's disease". Journal of Alzheimer's Disease (IOS Press) 19 (2): 573–589. 2010. doi:10.3233/JAD-2010-1262. PMID 20110603.
- ↑ "High throughput artificial membrane permeability assay for blood-brain barrier". European Journal of Medicinal Chemistry 38 (3): 223–232. March 2003. doi:10.1016/S0223-5234(03)00012-6. PMID 12667689.
- ↑ "Identification of novel functional inhibitors of acid sphingomyelinase". PLOS ONE 6 (8). 2011. doi:10.1371/journal.pone.0023852. PMID 21909365. Bibcode: 2011PLoSO...623852K.
- ↑ "Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents". Proceedings of the National Academy of Sciences of the United States of America 110 (17): 7044–7049. April 2013. doi:10.1073/pnas.1303510110. PMID 23576755. Bibcode: 2013PNAS..110.7044K.
- ↑ "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure–Activity Insights". Journal of Medicinal Chemistry 68 (16): 17485–17498. 2025. doi:10.1021/acs.jmedchem.5c01008. PMID 40815226.
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