GSK2245035   Click here for help

GtoPdb Ligand ID: 9254

Synonyms: compound 32 [PMID: 26861551]
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: GSK2245035 is reported as a selective Toll-like receptor 7 (TLR7) agonist, with potential clinical action as an intranasally administered anti-asthmatic [2]. It is Example 22 claimed in patent WO2010018133 [3].

The TLR7- IFNα pathway is a novel pathway being investigated for pharmacological intervention in allergic asthma.
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 5
Hydrogen bond donors 2
Rotatable bonds 10
Topological polar surface area 102.06
Molecular weight 390.27
XLogP 3.19
No. Lipinski's rules broken 0

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 CCCC(Oc1nc(N)c2c(n1)n(CCCCCN1CCCCC1)c(=O)[nH]2)C
Isomeric SMILES CCC[C@@H](Oc1nc(N)c2c(n1)n(CCCCCN1CCCCC1)c(=O)[nH]2)C
InChI InChI=1S/C20H34N6O2/c1-3-10-15(2)28-19-23-17(21)16-18(24-19)26(20(27)22-16)14-9-5-8-13-25-11-6-4-7-12-25/h15H,3-14H2,1-2H3,(H,22,27)(H2,21,23,24)/t15-/m0/s1
InChI Key LFMPVTVPXHNXOT-HNNXBMFYSA-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
In vivo findings disclosed in WO2010018133 report that GSK2245035 (Example 22) induces IFNα production, with mean serum levels reaching 21029 pg/ml (none detected in control mice) [3]. Early clinical trial results show clear target engagement at a dose of 20ng (as detected by local and peripheral increase of IFN-gamma-inducible protein-10) and an accceptable safety profile doses acheiving a local TLR7-mediated immune response [6]. Doses above 100ng were associated with undesireable cytokine release syndrome-related symptoms.

Direct binding assays have not been performed for this compound, rather its engagement with TLR7 has been assessed in functional assays measuring ligand-induced increases in downstream cytokine production/release [2]. An EC50 of ~4.5nM for IFNα production in PBMCs is reported [2].
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
TLR7 Primary target of this compound Hs Agonist Agonist - - - 2
⤷ [2]