astemizole   Click here for help

GtoPdb Ligand ID: 2603

Synonyms: Hismanal®
Approved drug PDB Ligand
astemizole is an approved drug
Compound class: Synthetic organic
Comment: Astemizole was originally identified as a histamine H1 receptor antagonist. Astemizole use as an antihistamine was withdrawn from the US market in 1999 as it caused arrhythmias, probably due to blocking the hERG potassium channel (Kv11.1) [5].

A 2014 publication showed that astemizole's anti-proliferative effects in cancer cells is due to disruption of a protein-protein interaction required for the formation of the active polycomb repressive complex 2 (PRC2) [3]. PRC2 contains the histone methyltransferase EZH2, which is responsible for catalytic trimethylation of lysine 27 on histone H3 (H3K27me3), an epigenetic modification that is a hallmark of silent chromatin. Aberrant PRC2 activity is associated with cancer initiation and progression. Astemizole was shown to inhibit the interaction between EZH2 and a PRC2 structural protein called embryonic ectoderm development (EED) [1], and that this action destabilizes PRC2 and reduces its methylation activity.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 3
Hydrogen bond donors 1
Rotatable bonds 8
Topological polar surface area 42.32
Molecular weight 458.25
XLogP 5.81
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES COc1ccc(cc1)CCN1CCC(CC1)Nc1nc2c(n1Cc1ccc(cc1)F)cccc2
Isomeric SMILES COc1ccc(cc1)CCN1CCC(CC1)Nc1nc2c(n1Cc1ccc(cc1)F)cccc2
InChI InChI=1S/C28H31FN4O/c1-34-25-12-8-21(9-13-25)14-17-32-18-15-24(16-19-32)30-28-31-26-4-2-3-5-27(26)33(28)20-22-6-10-23(29)11-7-22/h2-13,24H,14-20H2,1H3,(H,30,31)
InChI Key GXDALQBWZGODGZ-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
Bioactivity Comments
Astemizole is one of a number of drugs that are cationic amphiphilic in nature, for which anti-SARS-CoV-2 activity has been identified in drug repurposing screens. Tummino et al. (2021; bioRxiv preprint PMID: 33791693 target="_blank") suggest that this antiviral activity is most likely a result of the drug promoting phospholipidosis via disruption of lipid homeostasis.
Selectivity at GPCRs
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
H1 receptor Primary target of this compound Hs Antagonist Antagonist 8.5 pKi - 4
⤷ pKi 8.5 (Ki 3x10-9 M) [4]
Selectivity at ion channels
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
Kv11.1 Hs Channel blocker - 9.0 pIC50 - 5
⤷ pIC50 9.0 (IC50 1x10-9 M) [5]
Kv10.1 Hs Channel blocker - 6.7 pIC50 - 2
⤷ pIC50 6.7 [2]