GW0742 (also known as GW610742 and fitorine) is a PPARδ/β agonist[2][3][4] that has been investigated for drug use by GlaxoSmithKline.[5]
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Pharmacodynamics
It is mixed PPAR-B agonist antagonist depending on its dosage.[6] It has weak activity on multiple nuclear receptors as well. It is antagonistic at androgen receptors and VDR.[6][7] In silico modelling suggest that it has effects on thyroid hormone receptors.[8]
Derivatives
Multiple derivatives of GW0742 core structure have been developed. One of the compounds has the thiazole ring replaced with an oxazole ring inhibited VDR-meditated transcription with IC50 of 660 nM.[7] Other novel analogues which are more potent than GWO742 with reduced toxicity have been developed as well.[9]
GW0742 has been shown to ameliorate experimentally induced pancreatitis in mice.[10] Additionally, it prevents hypertension in diet induced obese mice,[11] has been investigated as potential antidiabetic drug,[12] and has anti-inflammatory effects.[13][14][11]
Smith SA, Monteith GR, Robinson JA, Venkata NG, May FJ, Roberts-Thomson SJ (July 2004). "Effect of the peroxisome proliferator-activated receptor beta activator GW0742 in rat cultured cerebellar granule neurons". Journal of Neuroscience Research. 77 (2): 240–9. doi:10.1002/jnr.20153. PMID 15211590. S2CID 21295375. Haskova Z, Hoang B, Luo G, Morgan LA, Billin AN, Barone FC, et al. (July 2008). "Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARbeta/delta ligand GW0742". Inflammation Research. 57 (7): 314–21. doi:10.1007/s00011-007-7157-4. PMID 18622687. S2CID 25631088. Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR, Sternbach DD (May 2003). "Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)--synthesis and biological activity". Bioorganic & Medicinal Chemistry Letters. 13 (9): 1517–21. doi:10.1016/s0960-894x(03)00207-5. PMID 12699745. Nandhikonda P, Yasgar A, Baranowski AM, Sidhu PS, McCallum MM, Pawlak AJ, Teske K, Feleke B, Yuan NY, Kevin C, Bikle DD, Ayers SD, Webb P, Rai G, Simeonov A, Jadhav A, Maloney D, Arnold LA (June 2013). "Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor". Biochemistry. 52 (24): 4193–203. doi:10.1021/bi400321p. PMC 3724348. PMID 23713684. Perez Diaz N, Zloh M, Patel P, Mackenzie LS (January 2016). "In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties". Prostaglandins & Other Lipid Mediators. 122: 18–27. doi:10.1016/j.prostaglandins.2015.12.002. PMID 26686607. Paterniti I, Mazzon E, Riccardi L, Galuppo M, Impellizzeri D, Esposito E, Bramanti P, Cappellani A, Cuzzocrea S (July 2012). "Peroxisome proliferator-activated receptor β/δ agonist GW0742 ameliorates cerulein- and taurocholate-induced acute pancreatitis in mice". Surgery. 152 (1): 90–106. doi:10.1016/j.surg.2012.02.004. PMID 22521259. Toral M, Gómez-Guzmán M, Jiménez R, Romero M, Zarzuelo MJ, Utrilla MP, Hermenegildo C, Cogolludo Á, Pérez-Vizcaíno F, Gálvez J, Duarte J (September 2015). "Chronic peroxisome proliferator-activated receptorβ/δ agonist GW0742 prevents hypertension, vascular inflammatory and oxidative status, and endothelial dysfunction in diet-induced obesity". Journal of Hypertension. 33 (9): 1831–44. doi:10.1097/HJH.0000000000000634. PMID 26147382. S2CID 38565637.
