Antiplatelet and Antithrombotic Effects of a Novel Selective Phosphodiesterase 3 Inhibitor, NSP-513, in Mice and Rats.

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  • Hirose Hiroyasu
    Tsukuba Research Institute,Banyu Pharmaceutical Co.,Ltd.,Okubo 3,Tsukuba 300-2611,Japan
  • Kimura Toshifumi
    Tsukuba Research Institute,Banyu Pharmaceutical Co.,Ltd.,Okubo 3,Tsukuba 300-2611,Japan
  • Okada Megumu
    Tsukuba Research Institute,Banyu Pharmaceutical Co.,Ltd.,Okubo 3,Tsukuba 300-2611,Japan
  • Itoh Yoshiki
    Tsukuba Research Institute,Banyu Pharmaceutical Co.,Ltd.,Okubo 3,Tsukuba 300-2611,Japan
  • Ishida Fumiaki
    Tsukuba Research Institute,Banyu Pharmaceutical Co.,Ltd.,Okubo 3,Tsukuba 300-2611,Japan
  • Mochizuki Nobuo
    Odawara Research Center,Nippon Soda Co.,Ltd.,Takada 345,Odawara 250-0280,Japan
  • Nishibe Tadayuki
    Odawara Research Center,Nippon Soda Co.,Ltd.,Takada 345,Odawara 250-0280,Japan
  • Nishikibe Masaru
    Tsukuba Research Institute,Banyu Pharmaceutical Co.,Ltd.,Okubo 3,Tsukuba 300-2611,Japan

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Abstract

We investigated the effects of NSP-513, (R)-4, 5-dihydro-5-methyl-6-[4-(2-propyl-3-oxo-1-cyclo-hexenyl)amino]phenyl-3(2H)-pyridazinone, on phosphodiesterase(PDE)isozyme activities, in vitro platelet aggregation and in vivo thrombus formation.NSP-513 selectively inhibited human platelet PDE 3 isozyme with an IC50 value of 0.039μM.In an in vitro human platelet aggregation assay, the IC50 values(μM)of NSP-513 for platelet aggregation induced by collagen, U-46619, arachidonic acid, adenosine diphosphate(ADP), epinephrine and thrombin were 0.31, 0.25, 0.082, 0.66, 0.23 and 0.73, respectively.In a mouse pulmonary thromboembolism model, orally administered NSP-513 showed in vivo antithrombotic effects that were 320 to 470 times more potent than those of cilostazol.In a rat carotid arterial thrombosis model, intraduodenally administered NSP-513(0.1mg/kg), cilostazol(30mg/kg)and aspirin(30mg/kg)reduced thrombus formation by 75%, 66% and 48%, respectively.However, intravenously administered dipyridamole(10mg/kg)did not significantly prevent thrombus formation.These results demonstrate that NSP-513 has the potential to prevent not only in vitro platelet aggregation but also in vivo thrombus formation and indicate that the highly selective PDE 3 inhibitory effect of NSP-513 may make this compound useful for assessing the physiological role of PDE 3.

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