PYRIDAZINES .13. SYNTHESIS OF 6-ARYL-5-OXYGENATED SUBSTITUTED-3(2H)-PYRIDAZINONES AND EVALUATION AS PLATELET-AGGREGATION INHIBITORS

Several 6-aryl-5-oxygenated substituted pyridazinones have been synthe sized and evaluated in vitro for inhibition of platelet aggregation in duced by adenosine 5'-diphosphate (ADP), thrombin and collagen. All th e tested compounds (except 8 and 9) inhibited platelet aggregation in a dose-dependent manner. The IC50 of the most active substance, compou nd 2b, was around 60 mu M against ADP and collagen as inducers. The in hibition of platelet aggregation caused by test compounds was dependen t on the level of oxidation of the function at the 5-position, with th e order of IC50 values being R-OH (2a, b, 5)<R-CHO (6, 7)<<R-COOH (8, 9). None of the tested compounds increased the intracellular levels of cAMP, indicating a lack of inhibitory activity on cAMP phosphodiester ase (PDE III) in intact cells. These results suggest that the group pr esent at the 5 position of 6-aryl-5-substituted pyridazinones determin es the platelet aggregation-inhibitory activity, and that a mechanism other than PDE inhibition is responsible for this effect.