Nidufexor

Protein target name:

NR1H4

Mechanism of action:

Partial Agonist

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Transcription factor

Subclass:

Nuclear Receptor

HUGO ID:

HGNC:7967

Entrez gene ID:

9971

UNIPROT ID:

Q96RI1

Target alias:

BAR; FXR; HRR1; HRR-1; PFIC5; RIP14

Probe Details

Chemical Probes Portal ID:

CPP2204

Probe alias:

LMB763, cpd 1

PubChem CID:

118063735

ChEMBL ID:

CHEMBL4297626

SMILES string:

CN1C(C2=CC(Cl)=CC=C2OC3)=C3C(C(N(CC4=CC=CC=C4)CC5=CC=C(C(O)=O)C=C5)=O)=N1

InChi Key:

JYTIXGYXBIBOMN-UHFFFAOYSA-N

Orthogonal probe:

GW4064

Physico-chemical properties

Solubility - preferred solvent:

34 uM

NMR:

1H NMR (400 MHz, DMSO): δ 12.93 (s, 1H), 7.96–7.85 (m, 2H), 7.71 (dd, J = 7.1, 2.5 Hz, 1H), 7.42–7.20 (m, 8H), 7.06 (dd, J = 8.7, 1.9 Hz, 1H), 5.45 (d, J = 3.9 Hz, 2H), 5.25 (d, J = 9.2 Hz, 2H), 4.58 (d, J = 12.1 Hz, 2H), 4.12 (d, J = 16.6 Hz, 3H).

13C NMR (101 MHz, DMSO-d6): δ 167.07, 162.21, 151.98, 142.65, 139.18, 132.20, 132.67, 129.70, 129.50, 129.50, 128.53, 128.53, 127.43, 127.43, 127.43, 127.43, 127.43, 125.53, 122.24, 119.0, 117.09, 116.64, 64.51, 50.68, 48.24.

Validation in Cells and Model Organisms

In cell validation

On target activity in cells

Potency in cells:

EC50, Efficacy

7 nM 57% FXR HTRF, 32 nM 50% FXR BSEP-Luciferase

Potency assay (cells):

FXR coactivator interaction assay, BSEP-luciferase reporter gene assay. Cell lines used: HEK293T exogenously expressing the respective NHR, Primary Rat Hepatocytes

Off target activity in cells

Probe Selectivity in Cell:

Profiling across a panel of enzymes, ion channels, nuclear receptors, and GPCRs demonstrated the high selectivity of Nidufexor for FXR. No activation of human GPBAR1, as determined by measuring the increase of intracellular cAMP levels, no activation of other nuclear receptors such as AR, ERα, GR, PPARγ, PR, or PXR using a TR-FRET assay (EC50 > 30 μM) and no activation of RXR, LXR, GR, PPARγ, or ERα using a cell-based agonist assay (EC50 > 10 μM).

In vivo validation

Organism:

Mouse, Rat, Dog

Dose:

3, 10, 30, 100, 300 mg/Kg (Dose Escalation), 3 mg/Kg IV

Route of delivery:

OralIntravenous

Plasma half life:

3.9, 5.7, 6.3, 5.6, 6.3 h (R)5.5 (M), 4.4 (R), 6.8 (D) h

Systemic clearance:

9.8 (M), 5.6 (R), 3.6 (D) mL/min/kg

Cmax:

4.5, 12.4, 28.1, 80.9, 140.8 uM

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.9b01621

Reference (PMID):

31940200

Nidufexor

Probe Availability

Probe Information

Target Details

BAR; FXR; HRR1; HRR-1; PFIC5; RIP14

Probe Details

Physico-chemical properties

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Nidufexor

Probe Availability

Probe Information

Target Details

BAR; FXR; HRR1; HRR-1; PFIC5; RIP14

Probe Details

Physico-chemical properties

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?