cilofexor   Click here for help

GtoPdb Ligand ID: 10644

Synonyms: example 13/9 [US10485795B2] | GS-9674 | GS9674
PDB Ligand
Compound class: Synthetic organic
Comment: Cilofexor (GS-9674) is a nonsteroidal farnesoid X receptor (FXR) agonist. It was originally identified by Phenex Pharmaceuticals [2] and is being developed by Gilead Pharmaceuticals for hepatic anti-steatotic activity, and potential to treat nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH) [1,4]. Successful treatment of these liver conditions will most likely be achieved using combinations of antilipemic, anti-inflammatory and anti-fibrotic agents.
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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

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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 8
Topological polar surface area 108.92
Molecular weight 585.06
XLogP 6.49
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 OC(=O)c1ccnc(c1)N1CC(C1)(O)c1ccc(cc1Cl)OCc1c(onc1c1c(Cl)cccc1Cl)C1CC1
Isomeric SMILES OC(=O)c1ccnc(c1)N1CC(C1)(O)c1ccc(cc1Cl)OCc1c(onc1c1c(Cl)cccc1Cl)C1CC1
InChI InChI=1S/C28H22Cl3N3O5/c29-20-2-1-3-21(30)24(20)25-18(26(39-33-25)15-4-5-15)12-38-17-6-7-19(22(31)11-17)28(37)13-34(14-28)23-10-16(27(35)36)8-9-32-23/h1-3,6-11,15,37H,4-5,12-14H2,(H,35,36)
InChI Key KZSKGLFYQAYZCO-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
Cilofexor was selected for devlopment due to its intestinal bias, so as to reduce potential side-effects (HDL cholesterol lowering and elevation of blood markers of steatosis and inflammation; alanine aminotransferase and aspartate aminotransferase) that were observed for earlier iterations of this compound.
Selectivity at nuclear hormone receptors
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Farnesoid X receptor Hs Agonist Agonist >7.6 pEC50 - 3
⤷ pEC50 >7.6 (EC50 <2.5x10-8 M) [3]
Description: EC50 determined as the ability of cilofexor to modulate the interaction between the purified bacterial expressed FXR ligand binding domain (LBD) and a synthetic biotinylated peptide based on residues 676-700 of SRC1, in a TR-FRET assay.