Prostacyclin (PGI 2 ) 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}ac-etic acid (MRE-269). NS-304 is an orally available and potent agonist for the PGI 2 receptor (IP receptor). The inhibition constant (K i ) of MRE-269 for the human IP receptor was 20 nM; in contrast, the K i values for other prostanoid receptors were Ͼ2.6 M. 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.Five prostanoids, prostaglandin (PG) D 2 , PGE 2 , PGF 2␣ , prostacyclin (PGI 2 ), and thromboxane A 2 (TXA 2 ), are cyclooxygenase metabolites of arachidonic acid. These lipid mediators interact with specific G protein-coupled receptors (DP, EP 1 , EP 2 , EP 3 , EP 4 , FP, IP, and TP) and activate the corresponding intracellular signaling cascade (Narumiya et al., 1999;Breyer et al., 2001). PGI 2 , which is mainly produced in vascular endothelial cells (Moncada et al., 1976;Moncada and Vane, 1978), acts via the PGI 2 receptor (IP receptor) as a potent vasodilator and inhibitor of platelet aggregation (Namba et al., 1994), and it counteracts the actions of TXA 2 , a potent vasoconstrictor and initiator of platelet aggregation. Activation of the IP receptor leads to stimulation of adenylate cyclase through coupling to G s protein, with a resulting increase in intracellular cAMP levels (Adie et al., 1992), and to activation of phospholipase C through coupling to G q protein leading to elevation of cytosolic Ca 2ϩ concentrations (Vassaux et al., 1992).The expression of IP receptor mRNA has been observed in various organs, including the heart, lung, thymus, spleen, and kidney (Oida et al., 1995

PurposeTargeting the prostacyclin pathway is an effective treatment option for pulmonary arterial hypertension (PAH). Patients with PAH have a deficiency of prostacyclin and prostacyclin synthase. Selexipag is an orally available and selective prostacyclin receptor (IP receptor) agonist. Selexipag is hydrolyzed to its active metabolite ACT-333679, also a selective and potent agonist at the IP receptor.MethodsIn this phase I study the pharmacokinetics (PK) and tolerability of single and multiple ascending doses of selexipag were investigated in a double-blind, placebo-controlled manner in 64 healthy male subjects. An additional group of 12 subjects received an open-label dose of selexipag 400 μg in the fasted condition and after a meal.ResultsMaximum plasma concentrations of selexipag and ACT-333679 were reached within 2.5 and 4 h, respectively, with mean half-lives of 0.7–2.3 and 9.4–14.22 h. In the presence of food, exposure to ACT-333679 was decreased by 27 %. The most frequent adverse event was headache. Selexipag was well tolerated up to a single dose of 400 μg and multiple doses of 600 μg following an up-titration step. No relevant treatment-related effects on vital signs, clinical laboratory, and electrocardiogram (ECG) parameters were detected.ConclusionSelexipag exhibits a good tolerability profile and PK properties that warrant further investigation.

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