GW9508 Chemical Properties

Melting point:

90-92°C

Boiling point:

538.4±45.0 °C(Predicted)

Density 

1.222±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

DMSO: >20mg/mL

form 

white powder

pka

4.77±0.10(Predicted)

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.

Safety Information

Hazard Codes 

Xn,N

Risk Statements 

22-37/38-41-50/53

Safety Statements 

26-39-60-61

RIDADR 

UN 3077 9 / PGIII

WGK Germany 

3

GW9508 Usage And Synthesis

Description

GW9508 (885101-89-3) is a selective agonist at the free fatty acid receptor, FFA1/4, (GPR40 and GPR120).1 Displays anti-allodynic and anti-hyperalgesic effects in mouse inflammatory and neuropathic pain models.2 Inhibits LPA-induced proliferation of DU145 and PC-3 cells.3 Decreases hepatic lipid accumulation in a high fat diet steatosis mouse model.4 Promotes brown adipose tissue thermogenesis.5

Uses

GW9508 is a GPR40 full agonist, used to regulate glucose in rats. Can be applied to the treatment of diabetes type 2. GPR120 selective and potent agonist also used in the treatment of diabetes type 2 due to GPR120’s ability to mediate GLP-1 secretion, insulin sensitization and anti-obesity effects.

Uses

GW9508, a selective FFA1/GPR40 agonist, may be used to differentiate and characterize the free fatty acid receptor FFA1/GPR40. GW9508 is used to study the role of FFA1/GPR40 receptors in processes such as the free fatty acid enhancement of glucose-stimulated insulin release and type 2 diabetes. GW9508 is used to study the process by which FFA1/GPR40 receptors protect from ovariectomy-induced bone loss in vivo though inhibition of osteoclast differentiation and suppress complete Freund′s adjuvant (CFA)-Induced inflammatory chronic pain.

Definition

ChEBI: 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid is an aromatic amine.

Biological Activity

Potent and selective agonist for the free fatty acid receptor FFA 1 (GPR40) (pEC 50 values are 7.32, < 4.3 and < 4.3 for FFA 1 , FFA 2 and FFA 3 receptors respectively). Inactive against a range of other GPCRs, kinases, proteases, integrins and PPARs. Potentiates glucose-stimulated insulin secretion in MIN6 cells (pEC 50 = 6.14).

Biochem/physiol Actions

GW9508 is a selective FFA1/GPR40 agonist. GPR40 was formerly an orphan G protein-coupled receptor whose endogenous ligands have now been identified as free fatty acids (FFAs). The receptor, named FFA receptor 1, has been implicated in the pathophysiology of type 2 diabetes and is a drug target because of its role in FFA-mediated enhancement of glucose-stimulated insulin release. GW9508 showed greater than 500-fold selectivity for GPR40 over GPR41 and GPR43 and possessed a good in vitro and in vivo profile with excellent bioavailability. GW9508 stimulated intracellular Ca2+ mobilization in human embryonic kidney HEK-293 cells expressing GPR40 or GPR120, but not in the parent HEK-293 cell line. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. GW9508 potentiates the KCl-mediated increase in insulin secretion in MIN6 cells.

Synthesis

General procedure for the synthesis of 4-[[(3-phenoxyphenyl)methyl]amino]phenylacetic acid from 3-(4-aminophenyl)propionic acid and m-phenoxybenzaldehyde: To a solution of 3-phenoxybenzaldehyde (3.2 mL, 18.5 mmol) in dichloroethane (60 mL) was added 3-(4-aminophenyl)propionic acid (3.0 g, 18.5 mmol). The mixture was sonicated and subsequently transferred to a 20 mL microwave reaction flask. The reaction was carried out in a microwave reactor at 100 °C for 10 min. After completion of the reaction, the solution was transferred to a 500 mL round bottom flask and sodium triacetoxyborohydride (7.8 g, 36.9 mmol) was added in batches. The reaction mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture and the organic layer was separated. The organic layer was washed twice sequentially with water (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure and the crude product was purified by silica gel column chromatography with the eluent being a solvent mixture of hexane/ethyl acetate in the ratio of 1:1, v/v, with the addition of a trace amount of acetic acid. Pure 3-(4-((3-phenoxybenzyl)amino)phenyl)propanoic acid (5.5 g, 86% yield) was finally obtained as a low melting point solid. The product was confirmed by 1H NMR (CDCl3) and mass spectrometry (MS): 1H NMR (CDCl3) δ 2.40 (t, 2H), 2.63 (t, 2H), 4.21 (s, 2H), 6.09 (bs, 1H), 6.44-6.47 (m, 2H), 6.81-6.83 (m, 1H), 6.87-6.89 (m, 2H) , 6.94-6.97 (m, 2H), 7.07 (bs, 1H), 7.11-7.18 (m, 2H), 7.29-7.33 (m, 1H), 7.35-7.38 (m, 2H), 12.09 (bs, 1H); MS m/z = 348 (M + H+).

storage

Store at RT

References

[1] CELIA P BRISCOE. Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules[J]. British Journal of Pharmacology, 2009, 148 5: 619-628. DOI:10.1038/sj.bjp.0706770
[2] PRASANNA KARKI. Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40.[J]. Molecular Pain, 2015, 11: 6. DOI:10.1186/s12990-015-0003-8
[3] ZE LIU. Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells.[J]. Journal of Pharmacology and Experimental Therapeutics, 2015, 352 2: 380-394. DOI:10.1124/jpet.114.218974
[4] HORNG-YIH OU. Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway.[J]. Journal of molecular endocrinology, 2014, 53 2: 165-174. DOI:10.1530/jme-14-0003
[5] JIYOUNG KIM. Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378.[J]. The Journal of Biological Chemistry, 2016: 20551-20562. DOI:10.1074/jbc.m116.721480

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