Astemizole

Astemizole is a potent anti-histamine compound that antagonizes the histamine H1-receptor with IC50 of 4 nM. It is also identified less potent at muscarinic acetylcholine receptors with Ki of 2.4 µM.

The histamine H1 receptor, a member of Rhodopsin-like G-protein-coupled receptors, is activated by the biogenic amine histamine and is expressed throughout the body, particularly in smooth muscles, on vascular endothelial cells, in the central nervous system, and in the heart.

Astemizole targets imperative proteins included in tumor movement, to be specific, either à-go-go 1 (Eag1) and Eag-related quality (Erg) potassium channels. Moreover, Eag1 is thought to be an imperative marker for a few distinct tumors. Astemizole hinders Eag1 and Erg channel action, and in cells communicating the Eag1 channel it diminishes tumor cell expansion in vitro and in vivo. It ought to be noticed that some cardiovascular reactions have been reported for astemizole in a couple of uncommon cases. Nevertheless, astemizole remains as an extremely encouraging hostile to malignancy apparatus on the grounds that it shows anti-proliferative mechanisms, may serve as the basis to synthesize new anti-cancer agents, and has been previously administered clinically. [1]

Reference:
1.  Astemizole: an old anti-histamine as a new promising anti-cancer drug. Anticancer Agents Med Chem. 2011 Mar;11(3):307-14.

Marmoset cytochrome P450 2J2 mainly expressed in small intestines and livers effectively metabolizes human P450 2J2 probe substrates, astemizole and terfenadine.[Pubmed:26899760]

Xenobiotica. 2016 Nov;46(11):977-85.

1. Common marmoset (Callithrix jacchus), a New World Monkey, has potential to be a useful animal model in preclinical studies. However, drug metabolizing properties have not been fully understood due to insufficient information on cytochrome P450 (P450), major drug metabolizing enzymes. 2. Marmoset P450 2J2 cDNA was isolated from marmoset livers. The deduced amino acid sequence showed a high-sequence identity (91%) with cynomolgus monkey and human P450 2J2 enzymes. A phylogenetic tree revealed that marmoset P450 2J2 was evolutionarily closer to cynomolgus monkey and human P450 2J2 enzymes, than P450 2J forms in pigs, rabbits, rats or mice. 3. Marmoset P450 2J2 mRNA was abundantly expressed in the small intestine and liver, and to a lesser extent in the brain, lung and kidney. Immunoblot analysis also showed expression of marmoset P450 2J2 protein in the small intestine and liver. 4. Enzyme assays using marmoset P450 2J2 protein heterologously expressed in Escherichia coli indicated that marmoset P450 2J2 effectively catalyzed Astemizole O-demethylation and terfenadine t-butyl hydroxylation, similar to human and cynomolgus monkey P450 2J2 enzymes. 5. These results suggest the functional characteristics of P450 2J2 enzymes are similar among marmosets, cynomolgus monkeys and humans.

Astemizole-Histamine induces Beclin-1-independent autophagy by targeting p53-dependent crosstalk between autophagy and apoptosis.[Pubmed:26739061]

Cancer Lett. 2016 Mar 1;372(1):89-100.

Apoptosis and autophagy are genetically regulated, evolutionarily conserved processes that can jointly seal cancer cell fates, and numerous death stimuli are capable of activating either pathway. Although crosstalk between apoptosis and autophagy is quite complex and sometimes contradictory, it remains a key factor determining the outcomes of death-related pathologies such as cancer. In the present study, exposure of MCF-7 breast cancer cells to HIS and the H1 receptor antagonist AST both alone and together with HIS (AST-HIS) led to generation of intracellular ROS, which induced massive cellular vacuolization through dilation of the ER and mitochondria. Consequently, apoptosis by Bax translocation, cytochrome c release, and caspase activation were triggered. In addition, AST-HIS caused ER stress-induced autophagy in MCF-7 cells, as evidenced by an increased LC3-II/LC3-I ratio, with surprisingly no changes in Beclin-1 expression. Non-canonical autophagy was induced via p53 phosphorylation, which increased p53-p62 interactions to enhance Beclin-1-independent autophagy as evidenced by immunocytochemistry and immunoprecipitation. In the absence of Beclin-1, enhanced autophagy further activated apoptosis through caspase induction. In conclusion, these findings indicate that AST-HIS-induced apoptosis and autophagy can be regulated by ROS-mediated signaling pathways.

Possibility as an anti-cancer drug of astemizole: Evaluation of arrhythmogenicity by the chronic atrioventricular block canine model.[Pubmed:27262902]

J Pharmacol Sci. 2016 Jun;131(2):150-3.

Since Astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the atrioventricular block dogs in order to clarify its cardiac safety profile. An oral dose of 3 mg/kg prolonged the QT interval without affecting the QTc (n = 4), whereas that of 30 mg/kg increased the short-term variability of repolarization and induced premature ventricular contractions in each animal, resulting in the onset of torsade de pointes in 1 animal (n = 4). Thus, proarrhythmic dose of Astemizole would be lower than anti-cancer one, limiting its re-profiling as an anti-cancer drug.

Astemizole Derivatives as Fluorescent Probes for hERG Potassium Channel Imaging.[Pubmed:26985309]

ACS Med Chem Lett. 2016 Jan 20;7(3):245-9.

The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule fluorescent probes, based on the potent hERG channel inhibitor Astemizole, for the imaging of hERG channels in hERG-transfected HEK293 cells (hERG-HEK293) and human colorectal cancer cells (HT-29), are described. These probes are expected to be applied in the physiological and pathological studies of hERG channels.

A clinical drug library screen identifies astemizole as an antimalarial agent.[Pubmed:16816845]

Nat Chem Biol. 2006 Aug;2(8):415-6.

The high cost and protracted time line of new drug discovery are major roadblocks to creating therapies for neglected diseases. To accelerate drug discovery we created a library of 2,687 existing drugs and screened for inhibitors of the human malaria parasite Plasmodium falciparum. The antihistamine Astemizole and its principal human metabolite are promising new inhibitors of chloroquine-sensitive and multidrug-resistant parasites, and they show efficacy in two mouse models of malaria.

Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.[Pubmed:12190308]

J Med Chem. 2002 Aug 29;45(18):3844-53.

In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.

Astemizole (R 43512), a second-generation antihistamine drug to diminish allergic symptoms with a long duration of action, is a histamine H1-receptor antagonist, with an IC50 of 4 nM. Astemizole also shows potent hERG K+ channel blocking activity with an IC50 of 0.9 nM. Astemizole has antipruritic effects.

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