GW0742 explained

Iupac Name:[4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methyl phenoxy]-acetic acid[1] | image = GW0742 skeletal.svg| width =

| tradename =| MedlinePlus = | pregnancy_category = | legal_status = Investigational| routes_of_administration =

| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =

| CAS_number_Ref = | CAS_number = 317318-84-6| UNII_Ref = | UNII = 4PZK9FJC4Z| ATC_prefix = None| ATC_suffix = | PubChem = 9934458| IUPHAR_ligand = 2686| DrugBank = | ChemSpiderID_Ref =| ChemSpiderID = 8110086| KEGG = C15625| ChEBI = | ChEMBL = 38508

| C=21 | H=17 | F=4 | N=1 | O=3 | S=2 | smiles = FC(F)(F)c3c(F)cc(c1nc(c(s1)CSc2cc(c(OCC(=O)O)cc2)C)C)cc3| StdInChI_Ref = | StdInChI = InChI=1S/C21H17F4NO3S2/c1-11-7-14(4-6-17(11)29-9-19(27)28)30-10-18-12(2)26-20(31-18)13-3-5-15(16(22)8-13)21(23,24)25/h3-8H,9-10H2,1-2H3,(H,27,28)| StdInChIKey_Ref = | StdInChIKey = HWVNEWGKWRGSRK-UHFFFAOYSA-N}}

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]

Pharmacology

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.[7] In silico modelling suggest that it has effects on thyroid hormone receptors.[8]

Chemistry

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. Other novel analogues which are more potent than GWO742 with reduced toxicity have been developed as well.[9]

Research

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]

See also

References

Notes and References

  1. Web site: Cayman Chemical GW0742. 31 Mar 2013 .
  2. Smith SA, Monteith GR, Robinson JA, Venkata NG, May FJ, Roberts-Thomson SJ . Effect of the peroxisome proliferator-activated receptor beta activator GW0742 in rat cultured cerebellar granule neurons . Journal of Neuroscience Research . 77 . 2 . 240–9 . July 2004 . 15211590 . 10.1002/jnr.20153 . 21295375 .
  3. Haskova Z, Hoang B, Luo G, Morgan LA, Billin AN, Barone FC, Shearer BG, Barton ME, Kilgore KS . 6 . Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARbeta/delta ligand GW0742 . Inflammation Research . 57 . 7 . 314–21 . July 2008 . 18622687 . 10.1007/s00011-007-7157-4 . 25631088 .
  4. 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 . Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)--synthesis and biological activity . Bioorganic & Medicinal Chemistry Letters . 13 . 9 . 1517–21 . May 2003 . 12699745 . 10.1016/s0960-894x(03)00207-5 .
  5. Wagner N, Jehl-Piétri C, Lopez P, Murdaca J, Giordano C, Schwartz C, Gounon P, Hatem SN, Grimaldi P, Wagner KD . 6 . Peroxisome proliferator-activated receptor beta stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin . Cardiovascular Research . 83 . 1 . 61–71 . July 2009 . 19351742 . 10.1093/cvr/cvp106 . free .
  6. 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 . Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor . . 52 . 24 . 4193–203 . June 2013 . 23713684 . 3724348 . 10.1021/bi400321p .
  7. Teske KA, Bogart JW, Arnold LA . Novel VDR antagonists based on the GW0742 scaffold . . 28 . 3 . 351–354 . February 2018 . 29287957 . 6008168 . 10.1016/j.bmcl.2017.12.041 .
  8. Perez Diaz N, Zloh M, Patel P, Mackenzie LS . In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties . . 122 . 18–27 . January 2016 . 26686607 . 10.1016/j.prostaglandins.2015.12.002 .
  9. Teske KA, Rai G, Nandhikonda P, Sidhu PS, Feleke B, Simeonov A, Yasgar A, Jadhav A, Maloney DJ, Arnold LA . Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold . . 19 . 10 . 646–656 . October 2017 . 28825467 . 5643073 . 10.1021/acscombsci.7b00066 .
  10. Paterniti I, Mazzon E, Riccardi L, Galuppo M, Impellizzeri D, Esposito E, Bramanti P, Cappellani A, Cuzzocrea S . Peroxisome proliferator-activated receptor β/δ agonist GW0742 ameliorates cerulein- and taurocholate-induced acute pancreatitis in mice . . 152 . 1 . 90–106 . July 2012 . 22521259 . 10.1016/j.surg.2012.02.004 .
  11. Toral M, Gómez-Guzmán M, Jiménez R, Romero M, Zarzuelo MJ, Utrilla MP, Hermenegildo C, Cogolludo Á, Pérez-Vizcaíno F, Gálvez J, Duarte J . Chronic peroxisome proliferator-activated receptorβ/δ agonist GW0742 prevents hypertension, vascular inflammatory and oxidative status, and endothelial dysfunction in diet-induced obesity . . 33 . 9 . 1831–44 . September 2015 . 26147382 . 10.1097/HJH.0000000000000634 . 38565637 .
  12. Niu HS, Ku PM, Niu CS, Cheng JT, Lee KS . Development of PPAR-agonist GW0742 as antidiabetic drug: study in animals . . 9 . 5625–32 . 2015 . 26508837 . 4610778 . 10.2147/DDDT.S95045 . free .
  13. Di Paola R, Esposito E, Mazzon E, Paterniti I, Galuppo M, Cuzzocrea S . GW0742, a selective PPAR-beta/delta agonist, contributes to the resolution of inflammation after gut ischemia/reperfusion injury . . 88 . 2 . 291–301 . August 2010 . 20430778 . 10.1189/jlb.0110053 . 21168990 .
  14. Haskova Z, Hoang B, Luo G, Morgan LA, Billin AN, Barone FC, Shearer BG, Barton ME, Kilgore KS . Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARbeta/delta ligand GW0742 . . 57 . 7 . 314–21 . July 2008 . 18622687 . 10.1007/s00011-007-7157-4 . 25631088 .

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