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

Abstract

2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) is an orally available, longacting 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 EP 3 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 EP 3 agonist, sulprostone, induced SPA and LPA vasoconstriction, and an EP 3 antagonist attenuated the vasoconstriction. Beraprost showed EP 3 agonism and induced LPA and SPA vasoconstriction, whereas the EP 3 antagonist inhibited this vasoconstriction and enhanced beraprost-and iloprost-induced SPA vasodilation. These findings suggest that the EP 3 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.Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by a progressive increase in pulmonary arterial pressure and pulmonary vascular resistance, leading ultimately to right ventricular failure and death (Rich et al., 1987;Farber and Loscalzo, 2004). The pathogenesis of PAH includes at least three processes occurring in small pulmonary arteries (SPA): vasoconstriction, vascular remodeling, and thrombosis (Rubin, 1997;Runo and Loyd, 2003).Prostacyclin (PGI 2 ) is a potent endogenous vasodilator and inhibitor of platelet aggregation that acts at the PGI 2 receptor (IP receptor) (Namba et al., 1994). PGI 2 contributes to the maintenance of homeostasis and has various other physiological effects in many organ systems (Narumiya et al., 1999 ABBREVIATIONS: PAH, pulmonary arterial hypertension; SPA, small pulmonary arteries; PGI 2 , prostacyclin; IP receptor, PGI 2 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)(isopropy...

Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension

“…The active metabolite of selexipag has a relatively long elimination half-life of 7.9 h that permits twice-daily dosing and contrasts with prostacyclin analogues that require continuous or very frequent dosing to achieve a sustained response [16,23]. Adverse events related to prostacyclin analogues are often due to the abrupt changes of the plasma levels of the drug.…”

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms

“…However, the progression of analog therapies to the clinic has been obstructed by off-target actions and unacceptable adverse effects caused by rapid vasodilatory fluctuations (14). The nonprostanoid IP receptor agonist, MRE-269 and its prodrug form, selexipag, which were developed to circumvent these limitations, have an extended elimination half-life (over 4 h in rats) (14) and a binding affinity for the human IP receptor that is 130-fold greater than that for other human prostanoid receptors (20). In the phase 3 GRIPHON (Prostacyclin [PGI 2 ] Receptor Agonist in Pulmonary Arterial Hypertension) study, selexipag treatment reduced the occurrence of the primary end point of death from any cause or a complication related to pulmonary arterial hypertension (hazard ratio 0.60; 99% CI 0.46-0.78; P , 0.001) (16).…”

“…MIN6 C3 cells were provided by Dr. Philippe Halban (University of Geneva, Switzerland) with permission from Dr. Jun-ichi Miyazaki, University of Osaka, who produced the maternal MIN6 cell line (19). Cells were treated with MRE-269 (Cayman Chemical, Ann Arbor, MI) in 0.1% DMSO at a concentration of 10 mmol/L (14,20), with or without preincubation for 30 min with the PKA inhibitor H89 (10 mmol/L) (Sigma-Aldrich, Oakville, Ontario, Canada) (21), or with the IP receptor inhibitor RO1138452 10 mmol/L (Cayman Chemical), 100 nmol/L insulin (Eli Lilly, Toronto, Ontario, Canada), or 10 mmol/L forskolin (Tocris Bioscience, Bristol, U.K.) for 1 h. IP receptor expression was determined in MIN6 B1 cells, human podocytes, and conditionally immortalized mouse podocytes (22).…”

Prostanoids in the treatment of pulmonary arterial hypertension

“…Hayvan deneylerinde etkinlik, plazmadaki devamlılık ve güvenilirlik yönünden beraprosttan üstün bulunmuştur (8). Monokrotaline ile indüklenmiş PH olan tavşanlarda vasküler endoteliyal fonksiyonu iyileştirmiş, pulmoner arteriyel duvar hipertrofisini geriletmiş, sağ ventrikül sistolik basıncını düşürmüş ve sağkalımı arttırmıştır (33). Henüz insan çalışmaları yoktur.…”