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Research ArticleCARDIOVASCULAR

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

Keiichi Kuwano, Asami Hashino, Tetsuo Asaki, Taisuke Hamamoto, Tetsuhiro Yamada, Kaori Okubo and Kenji Kuwabara
Journal of Pharmacology and Experimental Therapeutics September 2007, 322 (3) 1181-1188; DOI: https://doi.org/10.1124/jpet.107.124248
Keiichi Kuwano
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Asami Hashino
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Tetsuo Asaki
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Taisuke Hamamoto
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Tetsuhiro Yamada
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Kaori Okubo
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Kenji Kuwabara
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Abstract

Prostacyclin (PGI2) and its analogs are useful for the treatment of various vascular disorders, but their half-lives are too short for widespread clinical application. To overcome this drawback, we have synthesized a novel diphenylpyrazine derivative, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), a prodrug of the active form {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269). NS-304 is an orally available and potent agonist for the PGI2 receptor (IP receptor). The inhibition constant (Ki) of MRE-269 for the human IP receptor was 20 nM; in contrast, the Ki values for other prostanoid receptors were >2.6 μM. MRE-269 was therefore a highly selective agonist for the IP receptor. The plasma concentrations of MRE-269 remained near peak levels for more than 8 h after oral administration of NS-304 to rats and dogs, and NS-304 increased femoral skin blood flow in rats in a long-lasting manner without affecting the hemodynamics. These findings indicate that NS-304 acts as a long-acting IP receptor agonist in vivo. The continuous vasodilation evoked by NS-304 was not attenuated by repeated treatment, indicating that NS-304 is unlikely to cause severe desensitization of the IP receptor in rats. Moreover, a microdose pharmacokinetic study in which NS-304 was orally administered to healthy male volunteers showed conversion of NS-304 to MRE-269 and a long plasma elimination half-life for MRE-269 (7.9 h). In conclusion, NS-304 is an orally available and long-acting IP receptor agonist prodrug, and its active form, MRE-269, is highly selective for the IP receptor. Therefore, NS-304 is a promising drug candidate for various vascular diseases, especially pulmonary arterial hypertension and arteriosclerosis obliterans.

Footnotes

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

  • doi:10.1124/jpet.107.124248.

  • ABBREVIATIONS: PG, prostaglandin; PGI2, prostacyclin; TXA2, thromboxane A2; DP, PGD2 receptor; EP, PGE2 receptor; FP, PGD2α receptor; TP, TXA2 receptor; 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; CHO, Chinese hamster ovary; h, human; LC/MS, high-performance liquid chromatography coupled to mass spectrometry; FSBF, femoral skin blood flow; MAP, mean arterial blood pressure; HR, heart rate; LC/MS/MS, high-performance liquid chromatography coupled to tandem mass spectrometry; r, rat; SQ-29548, [1S-[1α,2α(Z),3α4α]]-7-[3-[[2-[(phenyl)amino)carbonyl]hydrazine]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; ONO-1301, {7,8-dihydro-5-[(E)-2-[(α-(3-pyridyl)benzylidene)amino-oxy]ethyl]-1-naphtyloxy} acetic acid; BMY 42393, 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy] acetic acid; BMY 45778, [3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]-phenoxy]acetic acid.

  • Received April 11, 2007.
  • Accepted May 31, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 3
1 Jun 2022
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Research ArticleCARDIOVASCULAR

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

Keiichi Kuwano, Asami Hashino, Tetsuo Asaki, Taisuke Hamamoto, Tetsuhiro Yamada, Kaori Okubo and Kenji Kuwabara
Journal of Pharmacology and Experimental Therapeutics September 1, 2007, 322 (3) 1181-1188; DOI: https://doi.org/10.1124/jpet.107.124248

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Research ArticleCARDIOVASCULAR

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

Keiichi Kuwano, Asami Hashino, Tetsuo Asaki, Taisuke Hamamoto, Tetsuhiro Yamada, Kaori Okubo and Kenji Kuwabara
Journal of Pharmacology and Experimental Therapeutics September 1, 2007, 322 (3) 1181-1188; DOI: https://doi.org/10.1124/jpet.107.124248
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