AMG-837

Protein target name:

FFAR1

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:

GPCR

Subclass:

Free fatty acid receptor

HUGO ID:

HGNC:4504

Entrez gene ID:

2864

UNIPROT ID:

O14842

Target alias:

FFA1R, GPCR40, GPR40

Probe Details

Chemical Probes Portal ID:

CPP1760

Probe alias:

AMG837; AMG-837, cpd 8

PubChem CID:

46854655

ChEMBL ID:

CHEMBL1829173

SMILES string:

CC#C[C@@H](CC(=O)O)C1=CC=C(C=C1)OCC2=CC=CC(=C2)C3=CC=C(C=C3)C(F)(F)F

InChi Key:

ZOPNBMMVVZRSGH-NRFANRHFSA-N

Orthogonal probe:

FasiglifamTUG-469

Physico-chemical properties

NMR:

1H NMR (500MHz) (DMSO-d6) d 12.25 (1H, s); 7.93 (2H, d, J =10 Hz); 7.84 (3H, m); 7.71 (1H, d, J = 10 Hz); 7.55 (2H, m); 7.29 (2H, d, J = 10 Hz); 7.00 (2H, d, J = 10 Hz); 5.19 (2H, m); 3.95 (1H, m); 2.61 (2H, m); 1.78 (3H, s).

Validation in Cells and Model Organisms

In cell validation

On target activity in cells

Potency in cells:

EC50, Emax

120 nM, 29 % (AM-1638), 11 nM (IP), 4.8 nM (IS)

Potency assay (cells):

Aequorin Ca2+ assay, inositol phosphate (IP)accumulation assay, radiolabelled displacement assay, insulin secretion (IS) assay

Off target activity in cells

Probe Selectivity in Cell:

Inactive on the closely related GPCRs GPR41 and GPR43. No significant activity in cell-based assays against PPARα, δ, and γ. An external panel of 64 receptors also revealed no significant activity with the exception of weak inhibition (IC50 = 3 uM) on the a2-adrenergic receptor.

In vivo validation

Organism:

Mouse, Rat, Dog, Cyno

Dose:

0.8 (M), 0.5 (R) 0.5 (D) 0.5 (C) mg/Kg IV, 5 (M), 0.5 (R) 2 (D) 0.5 (C) mg/Kg PO

Route of delivery:

OralIntravenous

Plasma half life:

8 (M), 7.2 (R), 28 (D), 12.4 (C) h

Systemic clearance:

0.07 (M), 0.07 (R), 0.08 (D), 0.06 (C) L/h/kg

Fraction of probe bound to plasma protein:

67 (M), 84 (R), 100 (D), 88 (C) %

Cmax:

17 (M), 1.4 (R), 7.5 (D), 2.1 (C) uM

Primary Reference

Reference (doi):

10.1016/j.bmcl.2011.10.118 10.1371/journal.pone.0046300

Reference (PMID):

22217876 23056280

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

FFAR1 (GPR40) is a proposed therapeutic target for the treatment of diabetes due to its ability to mediate glucose stimulated insulin secretion (GSIS) from pancreatic beta-cells and incretin hormones (glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1)) release from enteroendocrine cells. Several small molecule partial and full agonists of FFAR1 have been developed. AMG-837 is a partial agonist of FFAR1 and in contrast to other full agonists, AMG-837 effects appear restricted to the pancreatic beta cell axis to increase GSIS. AMG-837 displays high target selectivity for FFAR1 and in vivo studies (e.g. oral glucose tolerance tests) performed in wild-type and FFAR1 KO mice demonstrate effects of AMG-837 upon glucose excursion are dependent upon FFAR1 (10.1016/j.bmcl.2011.10.118). AMG-837 is therefore a suitable orthogonal probe that could be used in addition to other partial and full agonist probes to explore the activity of FFAR1.

Mar 29 2021 - 9:42pm

My rating refers to using this compound as a partial agonist ONLY. Other compounds are available that display full agonist properties, as described in 10.1371/journal.pone.0046300. Based on the available data AMG-837 can be used in cell based assays, primary pancreatic islet assays and in animal models within the stated concentrations (see comment re reviewer’s limited knowledge of pharmacokinetics below).

In this case, it was difficult to decide on the most appropriate rating. A 3-star rating suggests that this is the best available tool, which seems too generous of a statement in this case given the limitations I mentioned. On the other hand, a 2-star rating suggests that the characterization was incomplete and inconclusive. In this case, I think the data is there and relatively complete, so this rating seems too harsh. Yet, although I do think that this compound is suitable for use, I do think that there have been developments in this space since 2012 that reported better probes/tool compounds for this target. Additionally, as mentioned, I really urge potential users to read the background literature before using this or any other tools for this target.

However, there are couple of issues to note:

- a potential target space beyond small number (<70 GPCRs out of more than 800) has not been examined

- no negative control compounds are available

- highly bound ( 98.7%) to human plasma; this did not interfere with results in rat (reference: https://doi.org/10.1371/journal.pone.0027270), and Cmax in mouse, rat, dog and monkey was in low M range (reference: DOI 10.1016/j.bmcl.2011.10.118).

General comments:

- Full agonists for FFAR1 (GPR40) have been reported; depending on type of questions being asked, full agonists may be more appropriate than a compound like AMG-837, which is a partial agonist with ago-allosteric mechanism.

- AMG-837 compound affects only signaling through Gq (and not Gs) pathway.

- The compound (AMG-837) and its target (FFAR1) have complicated pharmacology (mechanism of action), with a lot of mechanistic subtlety so this reviewer recommends spending time with primary and review literature to learn about the target and the compounds (including endogenous ligands) that it binds.

- AMG-837 and structurally related compounds display significantly different pharmacology, suggesting that SAR is hard to deduce.

- AMG-837 is highly lipophilic (cLog P = 7.6) and likely to have significant CNS exposure, so care needs to be taken when used in vivo to account for possible CNS exposure.

- Reviewer is not an expert on pharmacokinetics, so take the comments re in vivo dose and use with these limitations in mind.

Additional background references: doi: 10.1124/mol.112.079640; 10.1016/j.molmet.2014.10.002; 10.1016/j.bmcl.2021.127969; 10.1021/ml400501

Apr 10 2021 - 12:47pm

AMG-837

Probe Availability

Probe Information

Target Details

FFA1R, GPCR40, GPR40

Probe Details

Physico-chemical properties

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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AMG-837

Probe Availability

Probe Information

Target Details

FFA1R, GPCR40, GPR40

Probe Details

Physico-chemical properties

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?