Prostaglandin E2 (PGE2) activates four E prostanoid (EP) receptors, EP1-4. EP4 is a Gs protein-coupled receptor that, by elevating the second messenger cAMP, plays important roles in bone formation and resorption, cancer, and atherosclerosis.1,2,3 CAY10598 is a very potent agonist of EP4, binding with a Ki value of 1.2 nM.4 Moreover, it does not bind EP1, EP2, EP3, or other prostanoid receptors, including DP, FP, IP, and TP.4 First generation EP4 receptor-selective agonists have been shown to reduce inflammation, improve bone healing, provide cardio- and neuroprotection, and reduce renal dysfunction, suggesting some clinical applications for EP4 agonists.5,6,7,8,9
1
Li, M., Thompson, D.D., and Paralkar, V.M. Prostaglandin E2 receptors in bone formation. Int Orthop 31 767-772 (2007).
2
Hawcroft, G., Ko, C.W.S., and Hull, M.A. Prostaglandin E2-EP4 receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells. Oncogene 26 3006-3019 (2007).
3
Babaev, V.R., Chew, J.D., Ding, L., et al. Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis. Cell Metab 8 492-501 (2008).
4
Billot, X., Chateauneuf, A., Chauret, N., et al. Discovery of a potent and selective agonist of the prostaglandin EP4 receptor. Bioorg Med Chem Lett 13 1129-1132 (2003).
5
Yamane, H., Sugimoto, Y., Tanaka, S., et al. Prostaglandin E2 receptors, EP2 and EP4, differentially modulate TNF-α and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils. Biochem Biophys Res Commun 278 224-228 (2000).
6
Marui, A., Hirose, K., Maruyama, T., et al. Prostaglandin E2 EP4 receptor-selective agonist facilitates sternal healing after harvesting bilateral internal thoracic arteries in diabetic rats. J Thorac Cardiovasc Surg 131(3) 587-593 (2006).
7
Xiao, C., Yuhki, K., Hara, A., et al. Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4. Circulation 109 2462-2468 (2004).
8
Ahmad, A.S., Ahmad, M., de Brum-Fernandes, A.J., et al. Prostaglandin EP4 receptor agonist protects against acute neurotoxicity. Brain Res 1066 71-77 (2005).
9
Li, J.H., Chou, C., Li, B., et al. A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus. J Clin Invest 119(10) 3115-3126 (2009).