| Uses | Astemizole is a histamine H1-receptor antagonist with IC50 of 4.7 nM. Astemizole is also a potent inhibitor of ether à-go-go 1 (Eag1) and Eag-related gene (Erg) potassium channels. Astemizole has antineoplastic and antipruritic effects. |
| Description | Astemizole belongs to the second-generation class of non-sedating, non-anticholinergicantihistamines. Its non-sedating properties appear to result from itspoor penetration of the blood brain barrier. As a result it shows no potentiationof CNS depressants, including alcohol. Its long half-life allows once-daily dosing. |
| Chemical Properties | Crystalline Solid |
| Originator | Janssen (Belgium) |
| Uses | Nonsedating-type histamine H1-receptor antagonist. Potential for combination therapy with antivancer drugs such as doxorubicin in resistant leukemia. Antihistaminic |
| Uses | scabicide |
| Uses | Astemizole is used for preventing and treating severe seasonal and chronic allergic rhinitis,allergic conjunctivitis, hives, Quinke’s edema, other allergic conditions and dermatitis.Synonyms of this drug are hismanal, histazol, and others. |
| Definition | ChEBI: A piperidine compound having a 2-(4-methoxyphenyl)ethyl group at the 1-position and an N-[(4-fluorobenzyl)benzimidazol-2-yl]amino group at the 4-position. |
| Manufacturing Process | A mixture of 2.3 parts of 2-(4-methoxyphenyl)ethyl methanesulfonate, 4.9parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 3.2 parts of sodium carbonate, 0.1 part of potassiumiodide and 90 parts of N,N-dimethylformamide is stirred overnight at 70°C.The reaction mixture is poured onto water. The product is extracted withmethylbenzene. The extract is washed with water, dried, filtered andevaporated. The residue is purified by column-chromatography over silica gelusing a mixture of trichloromethane and methanol (98:2 by volume) aseluent. The pure fractions are collected and the eluent is evaporated. Theresidue is crystallized from 2,2'-oxybispropane, yielding 2.2 parts (48%) of 1-(4-fluorophenylmethyl)-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1Hbenzimidazol-2-amine, MP 149.1°C. |
| Brand name | Hismanal (Janssen);Alermizol;Astezol;Astol;Histamanal;Novo-nastizol;EISMANAL. |
| Therapeutic Function | Antiallergic, Antihistaminic |
| World Health Organization (WHO) | The first clinically interesting histamine ti-antagonists wereintroduced in the late forties and early fifties. Several histamine ti-antagonists havea similar cardiac effect to that seen with astemizole and terfenadine. Seriouscardiovascular adverse reactions have been reported when used concomitantly withimidazole antifungals and macrolide antibiotics. |
| Biological Activity | Orally active, potent histamine H 1 antagonist (IC 50 = 4 nM) that displays 20-fold, > 250-fold and > 250-fold selectivity over 5-HT, dopamine and muscarinic acetylcholine receptors respectively. Exhibits antimalarial activity in multidrug resistant strains in vitro (IC 50 = 227 - 734 nM). Also potent hERG K + channel blocker (IC 50 = 0.9 nM) that displays cardiotoxicity in vivo . |
| Biochem/physiol Actions | Astermizole is a potent hERG potassium channel blocker (IC50 of 0.9 nM) and may used as a pharmacological chaperone to correct folding defects and restore protein function for some mutated forms of hERG channels. It has also been studied for treatment of malaria, hERG and hEAG channel function in cancer and as a second generation antihistamine H-1 antagonist. |
| Safety Profile | Poison by subcutaneous andintravenous routes. Moderately toxic by ingestion. Humansystemic effects by ingestion: arrhythmias, coma, nauseaor vomiting, somnolence. When heated to decompositionit emits toxic fumes of F?? and NOx. |
| Synthesis | Astemizole, 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl) ethyl]-4-piperidinyl]-benzimidazol-2-amine (16.1.31), is synthesized in a multi-stage synthesis from1-carbethoxy-4-aminopiperidine and 2-nitroisothiocyanobenzol, from which a derivative ofthiourea (16.1.26) is synthesized upon their reaction. The nitro group of the product isreduced and the further S-methoxided. In reaction conditions intermolecular cyclization intoa derivative of benimidazol, N-[1-[2-(4-carethoxy)]-4-piperidinyl]benzimidazol-2-amine(16.1.28) occurs. The obtained aminobenzimidazole derivative is alkylated with 4-fluorobenzylchorideinto 1-[(flurophenyl)methyl]-N-[1-[2-(4-carethoxy)]-4-piperidinyl] benzimidazol-2-amine (16.1.29). The carbethoxyl group of the resulting compound (16.1.29) ishydrolyzed by hydrobromic acid, forming a non-substituted on the nitrogen atom derivativeof piperidine (16.1.30), the alkylation of which with 2-(4-methoxyphenyl)ethylmetanesulfonateleads to the formation of astemizole (16.1.31). |
| storage | Store at +4°C |
| References | [1] D M RICHARDS. Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy.[J]. Drugs, 1984, 28 1: 38-61. DOI:10.2165/00003495-198428010-00003
[2] P M LADURON. In vitro and in vivo binding characteristics of a new long-acting histamine H1 antagonist, astemizole.[J]. Molecular Pharmacology, 1982, 21 2: 294-300. |
