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 microM. 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.
Kuwano
Keiichi
K
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-Ku, Kyoto 601-8550, Japan. k.kuwano@po.nippon-shinyaku.co.jp
Hashino
Asami
A
Asaki
Tetsuo
T
Hamamoto
Taisuke
T
Yamada
Tetsuhiro
T
Okubo
Kaori
K
Kuwabara
Kenji
K
D000081:Acetamides / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D005269:Femur / Q000098:blood supply; D006207:Half-Life; D006801:Humans; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D044006:Receptors, Epoprostenol / Q000819:agonists*; D012039:Regional Blood Flow / Q000187:drug effects; D014652:Vascular Diseases / Q000188:drug therapy; D014664:Vasodilation / Q000187:drug effects
D000081:Acetamides; D011355:Prodrugs; D011719:Pyrazines; D044006:Receptors, Epoprostenol; C523468:selexipag