MRE-269 (ACT-333679)

Prostacyclin (PGI₂) is a potent vasorelaxant and inhibitor of platelet aggregation. It mediates its actions by binding to a specific G protein-coupled receptor, the IP receptor, on the surface of endothelial cells, arterial smooth muscle, and platelets.¹ The IP receptor also participates in signal transduction of the pain response, cardioprotection, and inflammation.^2,3,4,5 MRE-269 is the active form of the prodrug NS-304. It is a potent and selective agonist for the human IP receptor with a K_i value of 20 nM.⁶ In contrast to PGI₂, which has a half-life of 30 seconds to a few minutes in vivo, plasma concentrations of MRE-269 remain near peak levels for more than eight hours in rats and dogs.⁶ Unlike the PGI₂ analogues, beraprost and iloprost, MRE-269 lacks high affinity for the EP₃ receptor.⁷ As a result, MRE-269 induces vasodilation equally in large and small pulmonary arteries, whereas vasodilation of small arteries by beraprost and iloprost is reduced via EP₃-mediated vasoconstriction.⁷

1.Aristoff, P.A., Johnson, P.D., and Harrison, A.W.Synthesis of 9-substituted carbacyclin analoguesJ. Org. Chem.48(26)5341-5348(1983) 2.Murata, T., Ushikubi, F., Matsuoka, T., et al.Altered pain perception and inflammatory response in mice lacking prostacyclin receptorNature388(6643)678-682(1997) 3.Cheng, Y., Austin, S.C., Rocca, B., et al.Role of prostacyclin in the cardiovascular response to thromboxane A2Science296(5567)539-541(2002) 4.Cui, Y., Kataoka, Y., Satoh, T., et al.Protective effect of prostaglandin I2 analogs on ischemic delayed neuronal damage in gerbilsBiochem. Biophys. Res. Commun.265(2)301-304(1999) 5.McLaughlin, V.V., Genthner, D.E., Panella, M.M., et al.Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertensionN. Engl. J. Med.338(5)273-277(1998) 6.Kuwano, K., Hashino, A., Asaki, T., et al.2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrugJ. Pharmacol. Exp. Ther.322(3)1181-1188(2007) 7.Kuwano, K., Hashino, A., Noda, K., et al.A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary arteryJ. Pharmacol. Exp. Ther.326(3)691-699(2008)