GW 9662-d5

The peroxisome proliferator-activated receptor γ (PPARγ) is the nuclear receptor responsible for transducing the therapeutic activity of the thiazolidinediones (TZDs). TZDs are a group of structurally related synthetic PPARγ agonists with antidiabetic actions in vivo.^1,2 Rosiglitazone is a prototypical TZD and has served as a reference compound for this class.³ There are many PPARγ agonists, including 15-deoxy-δ^12,14-prostaglandin J₂ and azelaoyl PAF, which are naturally derived.^4,5 However, only a few antagonists have been reported.⁶ GW 9662 blocks the PPARγ-induced differentiation of monocytes to osteoclasts by >90% at a dose of 0.1 µM.⁷ It is therefore a much more potent antagonist than BADGE, which is another reported PPARγ antagonist.⁷

1.Willson, T.M., Cobb, J.E., Cowan, D.J., et al.The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinedionesJ. Med. Chem.39665-668(1996) 2.Maxey, K.M., Hessler, E., MacDonald, J., et al.The nature and composition of 15-deoxy-δ12,14-PGJ2Prostaglandins & Other Lipid Mediators6215-21(2000) 3.Wright, H.M., Clish, C.B., Mikami, T., et al.A synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiationThe Journal of Biological Chemisty2751873-1877(2000) 4.Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., et al.An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ)J. Biol. Chem.270(22)12953-12956(1995) 5.Cantello, B.C.C., Cawthorne, M.A., Cottam, G.P., et al.[[ω-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agentsJ. Med. Chem.373977-3985(1994) 6.Davies, S.S., Pontsler, A.V., Marathe, G.K., et al.Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor γ ligands and agonistsThe Journal of Biological Chemisty27616015-16023(2001) 7.Bendixen, A.C., Shevde, N.K., Dienger, K.M., et al.IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor γ1Proceedings of the National Academy of Sciences of the United States of America982443-2448(2001)