GW 7647

GW 7647 is a potent, selective, and cell-permeable peroxisome proliferator-activated receptor (PPAR) agonist, with EC₅₀ values of 6nM, 1.1μM, and 6.2μM for human PPARα, PPARγ, and PPARδ, respectively^[1]. GW 7647 activates receptors to regulate genes involved in fatty acid oxidation and is commonly used in research on insulin resistance, lipid metabolism, and inflammatory diseases^[2,3,4].

In vitro, treatment of APPswe-transfected SH-SY5Y cells with GW 7647 (50, 100μM) for 24h resulted in a dose-dependent decrease in β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity^[5]. In primary rat astrocytes pretreated with LPS (10ng/mL) for 46h to induce endotoxin tolerance, addition of GW 7647 (1μM) 15min prior to secondary LPS stimulation (100ng/mL; 4h) significantly inhibited LPS-induced cyclooxygenase-2 (Cox2) mRNA expression^[6].

In vivo, oral administration of GW 7647 (2.5mg/kg/day) to LDLR/Apobec-1 DKO/hA-ITg (LAA) mice for 24 weeks reduced total aortic atherosclerotic lesion area by 35% and aortic root lesion area by 31% compared to the control group^[7]. Pretreatment of rats with GW 7647 (3mg/kg; i.p.) 30min prior to LiCl-induced acute nausea model significantly suppressed LiCl-induced conditioned gaping and alleviated acute nausea^[8].

References:
[1] BROWN P J, STUART L W, HURLEY K P, et al. Identification of a subtype selective human PPARα agonist through parallel-array synthesis[J]. Bioorganic & Medicinal Chemistry Letters, 2001, 11(9): 1225-1227.
[2] YUE T, BAO W, JUCKER B M, et al. Activation of peroxisome proliferator–activated receptor-α protects the heart from ischemia/reperfusion injury[J]. Circulation, 2003, 108(19): 2393-2399.
[3] QU X X, HE J H, CUI Z Q, et al. PPAR-α agonist GW7647 protects against oxidative stress and iron deposit via GPx4 in a transgenic mouse model of Alzheimer's diseases[J]. ACS Chemical Neuroscience, 2021, 13(2): 207-216.
[4] OKISHIO S, YAMAGUCHI K, ISHIBA H, et al. PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat[J]. Scientific Reports, 2020, 10(1): 19578.
[5] ZHANG H, GAO Y, QIAO P, et al. PPAR-α agonist regulates amyloid-β generation via inhibiting BACE-1 activity in human neuroblastoma SH-SY5Y cells transfected with APPswe gene[J]. Molecular and Cellular Biochemistry, 2015, 408(1): 37-46.
[6] ASTAKHOVA A A, CHISTYAKOV D V, PANKEVICH E V, et al. Regulation of cyclooxygenase 2 expression by agonists of PPAR nuclear receptors in the model of endotoxin tolerance in astrocytes[J]. Biochemistry (Moscow), 2015, 80(10): 1262-1270.
[7] NAKAYA K, TOHYAMA J, NAIK S U, et al. Peroxisome proliferator-activated receptor-α activation promotes macrophage reverse cholesterol transport through a liver x receptor–dependent pathway[J]. Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(6): 1276-1282.
[8] ROCK E M, MORENO-SANZ G, LIMEBEER C L, et al. Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARα and CB1 receptors[J]. British Journal of Pharmacology, 2017, 174(21): 3837-3847.