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MRE-269 (ACT-333679) Sale

(Synonyms: [4-[(5,6-二苯基吡嗪基)(1-甲基乙基)氨基]丁氧基]乙酸,ACT-333679) 目录号 : GC34015

Selective IP receptor agonist

MRE-269 (ACT-333679) Chemical Structure

Cas No.:475085-57-5

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产品描述

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 Ki 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)

Chemical Properties

Cas No. 475085-57-5 SDF
别名 [4-[(5,6-二苯基吡嗪基)(1-甲基乙基)氨基]丁氧基]乙酸,ACT-333679
Canonical SMILES OC(COCCCCN(C(C)C)C1=NC(C2=CC=CC=C2)=C(C3=CC=CC=C3)N=C1)=O
分子式 C25H29N3O3 分子量 419.52
溶解度 DMSO : ≥ 50 mg/mL (119.18 mM);Water : < 0.1 mg/mL (insoluble) 储存条件 Store at -20°C
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Research Update

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.PMID:23872196DOI:10.1016/j.prostaglandins.2013.07.003.

The prostacyclin (IP) receptor agonists, treprostinil, iloprost and the selexipag metabolite, MRE-269 (ACT-333679) were evaluated in rat distal pulmonary blood vessels. Small pulmonary arteries and veins were pre-contracted with the thromboxane mimetic, U46619 (25 and 100nM, respectively), and relaxation determined with and without IP receptor antagonists, RO1138452 and RO3244794. In arteries, treprostinil was a more potent vasorelaxant than iloprost, while the efficacy of iloprost was greater. In pulmonary arteries, treprostinil-induced relaxation was essentially abolished by both IP antagonists (1μM), while responses to iloprost were partially inhibited. Both treprostinil and iloprost were equipotent, prominently relaxing pulmonary veins with responses being similarly and partially sensitive to IP antagonists. In contrast, RO1138452 failed to inhibit relaxations to MRE-269 in either pulmonary arteries or veins, suggesting no involvement of typical IP receptors. Thus, rat pulmonary tissues cannot be considered appropriate to assess classical IP receptors using the proposed highly selective non-prostanoid agonist MRE-269, contrasting with the IP receptor agonism profile of prostacyclin analogues, iloprost and treprostinil.

Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

Pharm Biol 2022 Dec;60(1):1-8.PMID:34860644DOI:10.1080/13880209.2021.2005636.

Context: As an inhibitor cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8), quercetin is a naturally occurring flavonoid with its glycosides consumed at least 100 mg per day in food. However, it is still unknown whether quercetin and selexipag interact. Objective: The study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles. Materials and methods: The ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate the pharmacokinetics of orally administered selexipag (2 mg/kg) with and without quercetin (2 mg/kg/day for 7 days) pre-treatment in beagles. The effect of quercetin on the pharmacokinetics of selexipag and its potential mechanism was studied through the pharmacokinetic parameters. Results: The assay method was validated for selexipag and ACT-333679, and the lower limit of quantification for both was 1 ng/mL. The recovery and the matrix effect of selexipag were 84.5-91.58% and 94.98-99.67%, while for ACT-333679 were 81.21-93.90% and 93.17-99.23%. The UPLC-MS/MS method was sensitive, accurate and precise, and had been applied to the herb-drug interaction study of quercetin with selexipag and ACT-333679. Treatment with quercetin led to an increased in Cmax and AUC0-t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively. Discussion and conclusion: The study indicated that quercetin could inhibit the metabolism of selexipag and ACT-333679 when co-administration. Therefore, the clinical dose of selexipag should be used with caution when co-administered with foods high in quercetin.

Selexipag Active Metabolite ACT-333679 Displays Strong Anticontractile and Antiremodeling Effects but Low β-Arrestin Recruitment and Desensitization Potential

J Pharmacol Exp Ther 2017 Jul;362(1):186-199.PMID:28476928DOI:10.1124/jpet.116.239665.

Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation, and extracellular matrix synthesis. Selexipag (Uptravi, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide) is the first nonprostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of selexipag and the main contributor to clinical efficacy ACT-333679 (previously known as MRE-269) behaved as a full agonist in multiple PAH-relevant receptor-distal-or downstream-cellular assays with a maximal efficacy (Emax) comparable to that of the prototypic PGI2 analog iloprost. In PASMC, ACT-333679 potently induced cellular relaxation (EC50 4.3 nM) and inhibited cell proliferation (IC50 4.0 nM) as well as extracellular matrix synthesis (IC50 8.3 nM). In contrast, ACT-333679 displayed partial agonism in receptor-proximal-or upstream-cAMP accumulation assays (Emax 56%) when compared with iloprost and the PGI2 analogs beraprost and treprostinil (Emax ∼100%). Partial agonism of ACT-333679 also resulted in limited β-arrestin recruitment (Emax 40%) and lack of sustained IP receptor internalization, whereas all tested PGI2 analogs behaved as full agonists in these desensitization-related assays. In line with these in vitro findings, selexipag, but not treprostinil, displayed sustained efficacy in rat models of pulmonary and systemic hypertension. Thus, the partial agonism of ACT-333679 allows for full efficacy in amplified receptor-distal PAH-relevant readouts while causing limited activity in desensitization-related receptor-proximal readouts.

Simultaneous quantification and pharmacokinetic investigation of selexipag and its main metabolite ACT-333679 in rat plasma by UPLC-MS/MS method

J Pharm Biomed Anal 2020 Oct 25;190:113496.PMID:32768890DOI:10.1016/j.jpba.2020.113496.

In the present study, an accurate, simple and fast bioanalytical method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique for simultaneous quantification of plasma selexipag and its main metabolite ACT-333679 concentrations in rats was optimized and established. The purpose of chromatographic separation of selexipag, ACT-333679 and the internal standard (IS, diazepam) was accomplished using an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 μm) column. The mobile phase was consisted of acetonitrile (solution A) and 0.1 % formic acid in water (solution B) in a linear gradient elution procedure with a flow rate of 0.40 mL/min. The measurement of the analytes and IS was explored using a XEVO TQ-S triple quadrupole tandem mass spectrometer, which was comprised with electrospray ionization (ESI) source in positive ion mode. Selected multiple reaction monitoring (MRM) mode was employed to detect the parent-to-daughter ion transitions as follows: m/z 497.4 → 302.2 for selexipag, m/z 420.1 → 378.2 for ACT-333679, and m/z 285.0 → 154.0 for diazepam (IS), respectively. The new UPLC-MS/MS method showed good linearity respectively at the calibration curve range of 0.05-50 ng/mL for selexipag, and 0.05-250 ng/mL for ACT-333679. The intra- and inter-day of accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery and matrix effect were also met the requirements. The newly developed UPLC-MS/MS assay was forward successfully used to describe the pharmacokinetic profiles of selexipag and ACT-333679 in rats after oral treatment with 6.0 mg/kg selexipag.

Differential effects of Selexipag [corrected] and prostacyclin analogs in rat pulmonary artery

J Pharmacol Exp Ther 2012 Dec;343(3):547-55.PMID:22918043DOI:10.1124/jpet.112.197152.

{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.