Y-590 (a new pyridazinone derivative), a potent anti-thrombotic agent--II. Inhibition of platelet phosphodiesterase.
The effects of 6-(2, 3, 4, 5-tetrahydro-5-methyl-3-oxo-pyridazine-6-yl)-1, 2, 3, 4-tetrahydro -1-methyl quinolin-2-one (Y-590) on platelet phosphodiesterases (PDE) were investigated. Y-590 incubated with washed rabbit platelets did not affect the cyclic AMP (cAMP) content. But when added to the washed platelets 1.5 minutes before prostaglandin I2 (PGI2), it potentiated the ability of the latter to increase cAMP. Y-590 potently inhibited cAMP-PDE in rabbit platelets, but its inhibitory effect on cGMP-PDE was less potent. Its G/A (IC50 for cGMP-PDE/IC50 for cAMP-PDE) was 1055, about 60 times that of papaverine. The concentration of Y-590 causing inhibition of cAMP-PDE was the same degree as that inhibiting platelet aggregation. These results indicate that Y-590 is a selective inhibitor of cAMP-PDE which exerts its anti-platelet activity by inhibiting cAMP degradation in platelets.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood; D005343:Fibrinolytic Agents; D066298:In Vitro Techniques; D008297:Male; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D015363:Quinolones; D011817:Rabbits
D005343:Fibrinolytic Agents; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D015363:Quinolones; C042821:Y 590; D010208:Papaverine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases