MRE-269-d₆

MRE-269-d₆ is intended for use as an internal standard for the quantification of MRE-269 (Item No. 10010412) by GC- or LC-MS. MRE-269 is an IP receptor agonist and an active metabolite of NS 304 (Item No. 10010411).¹ It is formed from NS 304 primarily via carboxylesterase 1 (CES1) in human liver microsomes and via CES2 in human intestinal microsomes.² It binds to the IP receptor (K_i = 20 nM) and increases cAMP levels in human pulmonary artery smooth muscle cells (PASMCs) in a concentration-dependent manner.^1,3 It is selective for the IP receptor over the DP receptor (IC₅₀ = 2.6 µM), EP₁, EP₂, EP₃, and EP₄ receptors (IC₅₀s = >10, 5.8, >10, and 4.9 µM, respectively), FP receptor (IC₅₀ = >10 µM), and TP receptor (IC₅₀ = >10 µM).¹ Due to its selectivity for IP over EP₃ receptors, MRE-269 induces vasodilation equally in both large and small isolated rat pulmonary arteries in a concentration-dependent manner.⁴ It also inhibits ADP-induced platelet aggregation in isolated human and rat platelet-rich plasma (IC₅₀s = 0.21 and 10 µM, respectively).¹ MRE-269 reduces PDGF-induced proliferation of primary PASMCs derived from patients with chronic thromboembolic pulmonary hypertension (CTEPH).⁵

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1. 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 prodrug. J. Pharmacol. Exp. Ther. 322(3), 1181-1188 (2007).

2. Imai, S., Ichikawa, T., Sugiyama, C., et al. Contribution of human liver and intestinal carboxylesterases to the hydrolysis of selexipag in vitro. J. Pharm. Sci. 108(2), 1027-1034 (2019).

3. Fuchikami, C., Murakami, K., Tajima, K., 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, porcine and human pulmonary arteries. Eur. J. Pharmacol. 795, 75-83 (2017).

4. 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 artery. J. Pharmacol. Exp. Ther. 326(3), 691-699 (2008).

5. Kuramoto, K., Ogawa, A., Kiyama, K., et al. Antiproliferative effect of selexipag active metabolite MRE-269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension. Pulm. Circ. 13(2), e12231 (2023).