NEW PYRIDAZINONE DERIVATIVES AS INHIBITORS OF PLATELET-AGGREGATION

The synthesis and evaluation of the biological activity of a series of 3(2H)-pyridazinone derivatives is reported. We assessed the in vitro activity of these compounds on aggregation and production of thromboxa ne A(2) and prostaglandin E(2) of human platelets. In compounds 11 and 14 the 3-phenylpropyl group is hr-linked to the 2 position of the pyr idazinone ring of 6-(1H-imidazole-1-yl)-3(2H)-pyridazinone 3 or -[4-(1 H-imidazole-1-yl)-phenyl]-3(2H)-pyridazinone 4, respectively. These co mpounds inhibited platelet aggregation induced by arachidonic acid, AD P and collagen, and simultaneously suppressed the synthesis of TxA(2) and increased the production of PGE(2). These results characterize com pounds 11 and 14 as thromboxane synthase inhibitors. However, the inhi bition of platelet aggregation induced by U46619 and of the first wave of ADP-induced aggregation, which is not normally observed with throm boxane synthase inhibitors, suggests additional mechanisms of action f or our compounds. On the basis of structural similarities with compoun ds described previously, these are possibly related to a phosphodieste rase inhibitory activity.