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

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} acetic 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 >2.6 mu 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.