GW9508

GW9508

Identifiers
IUPAC name 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid
CAS Number	885101-89-3
PubChem CID	11595431
IUPHAR/BPS	1050
ChemSpider	9770191
UNII	4T77GYP2CS
ChEBI	CHEBI:93259
ChEMBL	ChEMBL207881
CompTox Dashboard (EPA)	DTXSID70237088
ECHA InfoCard	100.161.077
Chemical and physical data
Formula	C22H21NO3
Molar mass	347.414 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1=CC=C(C=C1)OC2=CC=CC(=C2)CNC3=CC=C(C=C3)CCC(=O)O
InChI InChI=1S/C22H21NO3/c24-22(25)14-11-17-9-12-19(13-10-17)23-16-18-5-4-8-21(15-18)26-20-6-2-1-3-7-20/h1-10,12-13,15,23H,11,14,16H2,(H,24,25) Key:DGENZVKCTGIDRZ-UHFFFAOYSA-N

GW9508 is an experimental drug which acts as a mixed agonist for the free fatty acid receptors FFAR1 (GPR40) and FFAR4 (GPR120). It is around 60x more potent as an agonist at FFAR1, ^[1] but has nevertheless often been used as a model agonist for FFAR4 especially in tissues which lack FFAR1 or in the presence of FFAR1 antagonists, ^[2] due to a historical lack of availability of highly selective FFAR4 agonists. ^[3] It has antiinflammatory effects ^{[4] [5] [6]} and has also been used to study the role of FFAR1 and FFAR4 in various processes such as regulation of insulin ^[7] and ghrelin ^[8] release, immune system function, ^{[9] [10]} and maintenance of bone density. ^[11]

References

1. Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, et al. (2006). "Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: Identification of agonist and antagonist small molecules". British Journal of Pharmacology. 148 (5): 619–628. doi:10.1038/sj.bjp.0706770. PMC   1751878 . PMID   16702987.
2. Hudson BD, Shimpukade B, Milligan G, Ulven T (2014). "The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)". The Journal of Biological Chemistry. 289 (29): 20345–20358. doi: 10.1074/jbc.M114.561449 . PMC   4106347 . PMID   24860101.
3. Moniri NH (2016). "Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders". Biochemical Pharmacology. 110–111: 1–15. doi:10.1016/j.bcp.2016.01.021. PMC   6415295 . PMID   26827942.
4. Fujita T, Matsuoka T, Honda T, Kabashima K, Hirata T, Narumiya S (2011). "A GPR40 Agonist GW9508 Suppresses CCL5, CCL17, and CXCL10 Induction in Keratinocytes and Attenuates Cutaneous Immune Inflammation". The Journal of Investigative Dermatology. 131 (8): 1660–1667. doi:10.1038/jid.2011.123. PMID   21593768.
5. Souza PR, Walker ME, Goulding NJ, Dalli J, Perretti M, Norling LV (2020). "The GPR40 Agonist GW9508 Enhances Neutrophil Function to Aid Bacterial Clearance During E. Coli Infections". Frontiers in Immunology. 11: 573019. doi: 10.3389/fimmu.2020.573019 . PMC   7550532 . PMID   33133087.
6. Zou Y, Zhang B, Jiang K, Zhou X, Tang Q, Chen S, et al. (2025). "GPR40 inhibits microglia-mediated neuroinflammation via the NLRP3/IL-1β/Glutaminase pathway after subarachnoid hemorrhage". Biochemical Pharmacology. 238 116971. doi:10.1016/j.bcp.2025.116971. PMID   40318813.
7. Hashimoto T, Mogami H, Tsuriya D, Morita H, Sasaki S, Kumada T, et al. (2019). "G-protein-coupled receptor 40 agonist GW9508 potentiates glucose-stimulated insulin secretion through activation of protein kinase Cα and ε in INS-1 cells". PLOS ONE. 14 (9): e0222179. doi: 10.1371/journal.pone.0222179 . PMC   6733457 . PMID   31498851.
8. Gong Z, Yoshimura M, Aizawa S, Kurotani R, Zigman JM, Sakai T, et al. (2014). "G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro". American Journal of Physiology. Endocrinology and Metabolism. 306 (1): E28 –E35. doi:10.1152/ajpendo.00306.2013. PMID   24222669.
9. Dragano NR, Solon C, Ramalho AF, De Moura RF, Razolli DS, Christiansen E, et al. (2017). "Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation". Journal of Neuroinflammation. 14 (1) 91. doi: 10.1186/s12974-017-0869-7 . PMC   5405534 . PMID   28446241.
10. Li Y, Yu H, Lopes-Virella MF, Huang Y (2024). "GPR40/GPR120 Agonist GW9508 Improves Metabolic Syndrome-Exacerbated Periodontitis in Mice". International Journal of Molecular Sciences. 25 (17): 9622. doi: 10.3390/ijms25179622 . PMC   11394899 . PMID   39273569.
11. Wauquier F, Philippe C, Léotoing L, Mercier S, Davicco MJ, Lebecque P, et al. (2013). "The Free Fatty Acid Receptor G Protein-coupled Receptor 40 (GPR40) Protects from Bone Loss through Inhibition of Osteoclast Differentiation". The Journal of Biological Chemistry. 288 (9): 6542–6551. doi: 10.1074/jbc.M112.429084 . PMC   3585087 . PMID   23335512.

Further reading

• Nishinaka T, Yamashita T, Nakamoto K, Kasuya F, Tokuyama S (2014). "Involvement of the Long-Chain Fatty Acid Receptor GPR40 in Depression-Related Behavior". Journal of Pharmacological Sciences. 125 (1): 112–115. doi:10.1254/jphs.14001sc. PMID   24758921.
• Tsukahara T, Watanabe K, Watanabe T, Yamagami H, Sogawa M, Tanigawa T, et al. (2015). "Tumor Necrosis Factor α Decreases Glucagon-Like Peptide-2 Expression by Up-Regulating G-Protein–Coupled Receptor 120 in Crohn Disease". The American Journal of Pathology. 185 (1): 185–196. doi:10.1016/j.ajpath.2014.09.010. PMID   25447053.
• Liu Z, Hopkins MM, Zhang Z, Quisenberry CB, Fix LC, Galvan BM, et al. (2015). "Omega-3 Fatty Acids and Other FFA4 Agonists Inhibit Growth Factor Signaling in Human Prostate Cancer Cells". The Journal of Pharmacology and Experimental Therapeutics. 352 (2): 380–394. doi:10.1124/jpet.114.218974. PMC   4293432 . PMID   25491146.
• Quesada-López T, Cereijo R, Turatsinze JV, Planavila A, Cairó M, Gavaldà-Navarro A, et al. (2016). "The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes". Nature Communications. 7 13479. Bibcode:2016NatCo...713479Q. doi:10.1038/ncomms13479. PMC   5118546 . PMID   27853148.
• An T, Zhang X, Li H, Dou L, Huang X, Man Y, et al. (2020). "GPR120 facilitates cholesterol efflux in macrophages through activation of AMPK signaling pathway". The FEBS Journal. 287 (23): 5080–5095. doi:10.1111/febs.15310. PMID   32243091.
• Xiao J, Cai T, Fang Y, Liu R, Flores JJ, Wang W, et al. (2021). "Activation of GPR40 attenuates neuroinflammation and improves neurological function via PAK4/CREB/KDM6B pathway in an experimental GMH rat model". Journal of Neuroinflammation. 18 (1) 160. doi: 10.1186/s12974-021-02209-9 . PMC   8286626 . PMID   34275493.
• Sadamura Y, Thapa S, Mizunuma R, Kambe Y, Hirasawa A, Nakamoto K, et al. (2021). "FFAR1/GPR40 Contributes to the Regulation of Striatal Monoamine Releases and Facilitation of Cocaine-Induced Locomotor Activity in Mice". Frontiers in Pharmacology. 12: 699026. doi: 10.3389/fphar.2021.699026 . PMC   8417570 . PMID   34489696.