MRE-269 (ACT-333679)

MRE-269 is an active metabolite of selexipag, and acts as a selective IP receptor agonist.

MRE-269 induces endothelium-independent vasodilation of rat extralobar pulmonary artery (EPA). MRE-269 or other IP receptor agonists including epoprostenol, iloprost, treprostinil and beraprost increase cAMP levels in hPASMC[1]. MRE-269 induces concentration-dependent vasodilation in LPA(+), LPA(-), and SPA(-)[3].

The vasorelaxant effects of MRE-269 on rat small intralobar pulmonary artery (SIPA) and EPA are the same, while the other IP receptor agonists induce less vasodilation in SIPA than in EPA[1]. MRE-269 produces substantial relaxation of rat small pulmonary artery, although its effects are only significant at high concentrations of above 10 μM (pEC50, 4.98±0.22). By contrast, in rat small pulmonary veins, MRE-269 only produces minimal relaxation over the whole concentration range, with only significant relaxation occurring at the two highest doses of MRE-269 of 10 and 100 μM[2].

[1]. Fuchikami C, et al. A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcin [2]. Orie NN, et al. Differential actions of the prostacyclin analogues treprostinil and iloprost and the selexipag metabolite, MRE-269 (ACT-333679) in rat small pulmonary arteries and veins. Prostaglandins Other Lipid Mediat. 2013 Oct;106:1-7 [3]. Kuwano 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