GW9508

GW9508 is a potent and selective G protein-coupled receptors FFA1 (GPR40) and GPR120 agonist with pEC₅₀s of 7.32 and 5.46, respectively. GW9508 shows ~100-fold selectivity for GPR40 over GPR120. GW9508 is inactive against other GPCRs, kinases, proteases, integrins and PPARs. GW9508 is a glucose-sensitive insulin secretagogue and an ATP-sensitive potassium (K_ATP) channels opener. Anti-inflammatory and anti-atherosclerotic activities^[1][2][3][4]. IC50 & Target: pEC50: 7.32 (GPR40) and 5.46 (GPR120)^[1] In Vitro: GW9508 stimulates intracellular Ca²⁺ mobilization in HEK-293 cells expressing GPR40 (pEC₅₀ of 7.32) or GPR120 (pEC₅₀ of 5.46), but not in the parent HEK-293 cell line^[1].
GW9508 produces a concentration-dependent increase (pEC₅₀ of 6.14) in glucose-stimulated insulin secretion at high glucose levels (25 mM). This resulted in a 1.52-fold increase in insulin secretion with 20 μM GW9508 in the presence of 25 mM glucose, compared with 25 mM glucose alone. The ability of GW9508 (10 μM) to enhance insulin secretion from MIN6 cells is significantly enhanced as glucose concentrations are increased^[1].
GW9508 inhibits CCL17 and CCL5 expression in a pertussis toxin-sensitive manner. The inhibitory effect by GW9508 is abrogated by depletion of GPR40 with RNA interference. GW9508 further suppresses expression of IL-11, IL-24, and IL-33 induced in HaCaT cells by TNF-α and IFN-γ. GW9508 also inhibits CCL5 and CXCL10 production by normal human epidermal keratinocytes^[2]. In Vivo: Administration of GW9508 200 (μM) topically to the skin suppresses ear swelling in a repeated hapten application model (BALB/c and C57BL/6 mice) and contact hypersensitivity with downregulation of CCL5 and CXCL10, respectively^[2].