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Research ArticleCARDIOVASCULAR

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

Keiichi Kuwano, Asami Hashino, Kumiko Noda, Keiji Kosugi and Kenji Kuwabara
Journal of Pharmacology and Experimental Therapeutics September 2008, 326 (3) 691-699; DOI: https://doi.org/10.1124/jpet.108.138305
Keiichi Kuwano
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Asami Hashino
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Kumiko Noda
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Keiji Kosugi
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Kenji Kuwabara
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Abstract

2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) is an orally available, long-acting nonprostanoid prostacyclin receptor (IP receptor) agonist prodrug. In a rat model of pulmonary hypertension induced by monocrotaline (MCT), NS-304 ameliorated vascular endothelial dysfunction, pulmonary arterial wall hypertrophy, and right ventricular hypertrophy, and it elevated right ventricular systolic pressure and improved survival. {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), the active form of NS-304, is much more selective for the IP receptor than are the prostacyclin analogs beraprost and iloprost, which also have high affinity for the EP3 receptor. To investigate the effect of receptor selectivity on vasodilation of the pulmonary artery, we assessed the relaxant response to these IP agonists in rats. MRE-269 induced vasodilation equally in large pulmonary arteries (LPA) and small pulmonary arteries (SPA), whereas beraprost and iloprost induced less vasodilation in SPA than in LPA. An EP3 agonist, sulprostone, induced SPA and LPA vasoconstriction, and an EP3 antagonist attenuated the vasoconstriction. Beraprost showed EP3 agonism and induced LPA and SPA vasoconstriction, whereas the EP3 antagonist inhibited this vasoconstriction and enhanced beraprost- and iloprost-induced SPA vasodilation. These findings suggest that the EP3 agonism of beraprost and iloprost interfered with the SPA vasodilation resulting from their IP receptor agonism. Endothelium removal markedly attenuated the vasodilation induced by beraprost, but not that induced by MRE-269 or iloprost. Moreover, the vasodilation induced by beraprost and iloprost, but not that induced by MRE-269, was more strongly attenuated in LPA from MCT-treated rats than from normal rats. NS-304 is a promising alternative medication for pulmonary arterial hypertension with prospects for good patient compliance.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.138305.

  • ABBREVIATIONS: PAH, pulmonary arterial hypertension; SPA, small pulmonary arteries; PGI2, prostacyclin; IP receptor, PGI2 receptor; PH, pulmonary hypertension; MCT, monocrotaline; NS-304, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide; MRE-269, {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid; DBTSA, (2E)-3-(3′,4′-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)-acrylamide; CHO, Chinese hamster ovary; RVSP, right ventricular systolic pressure; HR, heart rate; RV/(LV+S), ratio of the weight of the right ventricle to that of the left ventricle plus septum; RVH, right ventricular hypertrophy; LPA, large pulmonary arteries; LPA(-), LPA without endothelium; LPA(+), LPA with endothelium; SPA(-), SPA without endothelium; Ki, inhibition constant.

    • Received February 21, 2008.
    • Accepted June 12, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleCARDIOVASCULAR

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

Keiichi Kuwano, Asami Hashino, Kumiko Noda, Keiji Kosugi and Kenji Kuwabara
Journal of Pharmacology and Experimental Therapeutics September 1, 2008, 326 (3) 691-699; DOI: https://doi.org/10.1124/jpet.108.138305

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Research ArticleCARDIOVASCULAR

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

Keiichi Kuwano, Asami Hashino, Kumiko Noda, Keiji Kosugi and Kenji Kuwabara
Journal of Pharmacology and Experimental Therapeutics September 1, 2008, 326 (3) 691-699; DOI: https://doi.org/10.1124/jpet.108.138305
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