GW9508 is a selective FFA1/GPR40 agonist (pEC50 values are 7.32, < 4.3 and < 4.3 for FFA1, FFA2 and FFA3 receptors respectively). GPR40 was formerly an orphan G protein-coupled receptor whose endogenous ligands have now been identified as free fatty acids (FFAs). 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 inhibited CCL17 and CCL5 expression in a pertussis toxin-sensitive manner. GW9508 also inhibited CCL5 and CXCL10 production by normal human epidermal keratinocytes. Administration of GW9508 topically to the skin in the challenging phase suppressed ear swelling in a repeated hapten application model and contact hypersensitivity with downregulation of CCL5 and CXCL10, respectively. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl-mediated increase in insulin secretion in MIN6 cells.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 20 mg/mL|
|Source||Exp Cell Res (2013). Figure 1. GW9508|
|Cell Lines||MC3T3-E1 cell|
|Concentrations||1 10 50 100 μM|
|Incubation Time||24 h|
|Results||To determine whether cell growth inhibition was related to cytostatic effects or cell death, OcP were labeled for apoptosis and necrosis pathways as determined by annexin V/7-AAD apoptosis detection kit. According to fluorescent activating cell sorting data, when incubated with 100 mM of GW9508, cells were found positive for both markers|
A GPR40 agonist GW9508 suppresses CCL5, CCL17, and CXCL10 induction in keratinocytes and attenuates cutaneous immune inflammation.
Fujita T, et al. J Invest Dermatol. 2011 Aug;131(8):1660-7. PMID: 21593768.
Activation of ATP-sensitive potassium channels in rat pancreatic beta-cells by linoleic acid through both intracellular metabolites and membrane receptor signalling pathway.
Zhao YF, et al. J Endocrinol. 2008 Sep;198(3):533-40. PMID: 18550787.
Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules.
Briscoe CP, et al. Br J Pharmacol. 2006 Jul;148(5):619-28. PMID: 16702987.
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