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

Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib.We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as

Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.

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