Antiplatelet and antithrombotic effects of a novel selective phosphodiesterase 3 inhibitor, NSP-513, in mice and rats.
We investigated the effects of NSP-513, (R)-4,5-dihydro-5-methyl-6-[4-(2-propyl-3-oxo-1-cyclohexenyl)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 0.039 microM. In an in vitro human platelet aggregation assay, the IC50 values (microM) 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 (0.1 mg/kg), cilostazol (30 mg/kg) and aspirin (30 mg/kg) reduced thrombus formation by 75%, 66% and 48%, respectively. However, intravenously administered dipyridamole (10 mg/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.
Hirose
H
H
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo, Japan.
Kimura
T
T
Okada
M
M
Itoh
Y
Y
Ishida
F
F
Mochizuki
N
N
Nishibe
T
T
Nishikibe
M
M
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C411871:4,5-dihydro-5-methyl-6-(4-(2-propyl-3-oxo-1-cyclohexenyl)amino)phenyl-3(2H)-pyridazinone; D005343:Fibrinolytic Agents; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011724:Pyridazines; D000244:Adenosine Diphosphate