astemizole   

GtoPdb Ligand ID: 2603

Synonyms: Hismanal®
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 Astemizole use as an antihistamine was withdrawn from the US market in 1999 as it caused arrhythmias, probably due to blocking the hERG potassium channel (Kv11.1) [5].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.
2D Structure
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Physico-chemical Properties
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
SMILES / InChI / InChIKey
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
Classification
Compound class Synthetic organic
Approved drug? Yes
Withdrawn drug? Yes
IUPAC Name
1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl]benzimidazol-2-amine
International Nonproprietary Names
INN number INN
4755 astemizole
Synonyms
Hismanal®
Database Links
BindingDB Ligand 24226
CAS Registry No. 68844-77-9
ChEBI CHEBI:2896
ChEMBL Ligand CHEMBL296419
DrugBank Ligand DB00637
DrugCentral Ligand 249
GtoPdb PubChem SID 135649968
PubChem CID 2247
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Wikipedia Astemizole

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Tocris
Astemizole
Cat. No. 3489