title: A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries.
abstract: Selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl)acetamide]) is a novel, orally available non-prostanoid prostacyclin receptor (IP receptor) agonist that has recently been approved for the treatment of pulmonary arterial hypertension (PAH). We examined the effect of the active metabolite of selexipag, MRE-269, and IP receptor agonists that are currently available as PAH therapeutic drugs on the relaxation of rat, porcine and human pulmonary artery. cAMP formation in human pulmonary artery smooth muscle cells was induced by all test compounds (MRE-269, epoprostenol, iloprost, treprostinil and beraprost sodium) and suppressed by IP receptor antagonists (CAY10441 and 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid). MRE-269 induced endothelium-independent vasodilation of rat extralobar pulmonary artery (EPA). In contrast, endothelial denudation or the addition of a nitric oxide synthase inhibitor markedly attenuated the vasodilation of EPA induced by epoprostenol, treprostinil and beraprost sodium but not iloprost. The vasorelaxant effects of MRE-269 on rat small intralobar pulmonary artery (SIPA) and EPA were the same, while the other IP receptor agonists induced less vasodilation in SIPA than in EPA. Furthermore, a prostaglandin E receptor 3 antagonist enhanced the vasodilation induced by all IP receptor agonists tested except MRE-269. We also investigated the relaxation induced by IP receptor agonists in pulmonary arteries from non-rodent species and found similar vasodilation modes in porcine and human as in rat preparations. These results suggest that MRE-269, in contrast to other IP receptor agonists, works as a selective IP receptor agonist, thus leading to pronounced vasorelaxation of rat, porcine and human pulmonary artery.
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan. Electronic address: c.fuchikami@po.nippon-shinyaku.co.jp.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Fuchikami
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan.
authors.forename: Koyuki
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan; R & D Administration Division, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Homan
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kosugi
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kuramoto
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Oka
authors.affiliation: R & D Administration Division, Nippon Shinyaku Co., Ltd, 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto601-8550, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kuwano
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D000085:Acetates / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D044006:Receptors, Epoprostenol / Q000819:agonists*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000085:Acetates; D011719:Pyrazines; D044006:Receptors, Epoprostenol; D014665:Vasodilator Agents; D009569:Nitric Oxide; C523468:selexipag; D000242:Cyclic AMP; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid
keywords: Human; MRE-269; NS-304; Prostacyclin receptor; Pulmonary arterial hypertension; Selexipag