Fasiglifam

Protein target name:

FFAR1

Mechanism of action:

Agonist

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

GPCR

Subclass:

Free fatty acid receptor

HUGO ID:

HGNC:4512

Entrez gene ID:

2864

UNIPROT ID:

O14842

Target alias:

FFA1R, GPCR40, GPR40

Probe Details

Chemical Probes Portal ID:

CPP1768

Probe alias:

TAK-875, AK875; TAK 875, cpd 9a

PubChem CID:

24857286

ChEMBL ID:

CHEMBL1829174

SMILES string:

CC1=CC(=CC(=C1C2=CC(=CC=C2)COC3=CC4=C(C=C3)[C@@H](CO4)CC(=O)O)C)OCCCS(=O)(=O)C

InChi Key:

BZCALJIHZVNMGJ-HSZRJFAPSA-N

Control compound:

cpd 9b

Orthogonal probe:

TUG-469AMG-837

PAINs evaluation:

PAINS-Free

Physico-chemical properties

NMR:

1H NMR (CDCl3) δ 1.99 (s, 6H), 2.29–2.41 (m, 2H), 2.61 (dd, J = 16.9, 9.2 Hz, 1H), 2.81 (dd, J = 16.9, 5.5 Hz, 1H), 2.97 (s, 3H), 3.23–3.31 (m, 2H), 3.75–3.87 (m 4.13 (t, J = 5.8 Hz, 2H), 4.28 (dd, J = 9.1, 6.0 Hz, 1H), 4.76 (t, J = 9.1 Hz, 1H), 5.06 (s, 2H), 6.44–6.52 (m, 2H), 6.64 (s, 2H), 7.02–7.10 (m, 2H), 7.16 (s, 1H), 7.35–7.46 (m, 2H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

38 nM (human)140 nM (rat)

Potency assay:

GPR40 radioactive Receptor Binding Assay

PDB ID for probe-target interaction (3D structure):

1GZM model

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

Selective against FFAR2, FFAR3 (no activity up to 10uM)

In cell validation

On target activity in cells

Potency in cells:

EC50

14 nM

Potency assay (cells):

FLIPR assay (Ca Efflux)

In vivo validation

Organism:

RatDog

Dose:

1 IV, 3 PO mg/Kg Rat0.5 IV, 1 PO mg/Kg Dog

Route of delivery:

OralIntravenous

Plasma half life:

4.1 (R)-7.5 (D) h

Systemic clearance:

34.2 (R), 29.8 (D) mL/h/kg

Fraction of probe bound to plasma protein:

76 (R), 92.4 (D) %

Cmax:

5.77 (R), 3.29 (D) ug/ml

Tmax:

1 (R), 2 (D) h

Primary Reference

Reference (doi):

10.1021/ml1000855 10.1124/jpet.111.183772

Reference (PMID):

24900210 21752941

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

Fasiglifam is an ago-allosteric modulator of free fatty acid receptor 1 (FFAR1(GPR40)), which amplifies the agonistic activity of the endogenous ligand c-linolenic acid (c-LA) by binding to an allosteric site of FFAR1. Fasiglifam alone exhibited partial agonistic activity in cells expressing moderate levels of FFAR1, and exerted positive cooperative effects with free fatty acids (FFAs) in vitro and in vivo. Fasiglifam displays excellent potency and selectivity for FFAR1 (EC50=14nM) over other members of the FFA receptor family (GPR41, GPR43, GPR120, for which EC50>10 μM). Partial agonistic activity of Fasiglifam as determined by intracellular calcium mobilization assays in CHO cells is dependent upon FFAR1 gene expression levels and augmentation of glucose-induced insulin secretion by fasiglifam, c-LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice (doi:10.1371/journal.pone.0076280) providing additional evidence for selectivity. Fasiglifam advanced into the clinic but was terminated due to idiosyncratic liver toxicity.

Mar 29 2021 - 9:27pm

Compound not tested for x-reactivity outside the FAR-family.
The liver safety aspect has been mechanistically investigated in https://pubmed.ncbi.nlm.nih.gov/30243991/ and https://pubmed.ncbi.nlm.nih.gov/28206647/
Primary Takeda patent filing with initial SAR is probably US20120046338 – Fused cyclic compounds

Apr 10 2021 - 1:13pm

Fasiglifam

Probe Availability

Probe Information

Target Details

FFA1R, GPCR40, GPR40

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Fasiglifam

Probe Availability

Probe Information

Target Details

FFA1R, GPCR40, GPR40

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?