Description
Prostacyclin (PGI
2) 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. The IP receptor also participates in signal transduction of the pain response, cardioprotection, and inflammation. 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. In contrast to PGI
2, 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. Unlike the PGI
2 analogues, beraprost and iloprost, MRE-
269 lacks high affinity for the EP
3 receptor. 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 EP
3-
mediated vasoconstriction.
Uses
MRE-269 an orally available and long-acting prostacyclin receptor agonist prodrug. MRE-269 is used for the treatment of pulmonary arterial hypertension. MRE-269 is an active metabolite of Selexipag (S253150).
Definition
ChEBI: A member of the class of pyrazines that is {4-[(propan-2-yl)(pyrazin-2-yl)amino]butoxy}acetic acid carrying two additional phenyl substituents at positions 5 and 6 on the pyrazine ring. The active metabolite of selexipag, an orphan drug used for the treatm
nt of pulmonary arterial hypertension.
in vivo
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].
References
[1] TAKAHIKO MURATA. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor[J]. Nature, 1997, 388 6643: 678-682. DOI:
10.1038/41780[2] YAN CHENG. Role of Prostacyclin in the Cardiovascular Response to Thromboxane A2[J]. Science, 2002, 296 5567. DOI:
10.1126/science.1068711[3] YILONG CUI . Protective Effect of Prostaglandin I2 Analogs on Ischemic Delayed Neuronal Damage in Gerbils[J]. Biochemical and biophysical research communications, 1999, 265 2: Pages 301-304. DOI:
10.1006/bbrc.1999.1671[4] V V MCLAUGHLIN. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension.[J]. New England Journal of Medicine, 1998, 338 5: 273-277. DOI:
10.1056/nejm199801293380501[5] KEIICHI KUWANO. 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]. Journal of Pharmacology and Experimental Therapeutics, 2007, 322 3: 1181-1188. DOI:
10.1124/jpet.107.124248[6] KEIICHI KUWANO. 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]. Journal of Pharmacology and Experimental Therapeutics, 2008, 326 3: 691-699. DOI:
10.1124/jpet.108.138305[7] NAOKI MATSUMOTO . The epoxy fatty acid pathway enhances cAMP in mammalian cells through multiple mechanisms[J]. Prostaglandins & other lipid mediators, 2022, 162: Article 106662. DOI:
10.1016/j.prostaglandins.2022.106662
![[4-[(5,6-Diphenylpyrazinyl)(1-methylethyl)amino]butoxy]-acetic acid Structure](https://www.chemicalbook.com/CAS2/GIF/475085-57-5.gif)
