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 thromboxane 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 pyridazinone ring of 6-(1H-imidazole-1-yl)-3(2H)-pyridazinone 3 or 6-[4-(1H-imidazole-1-yl)-phenyl]-3(2H)-pyridazinone 4, respectively. These compounds inhibited platelet aggregation induced by arachidonic acid, ADP and collagen, and simultaneously suppressed the synthesis of TxA(2) and increased the production of PGE(2). These results characterize compounds 11 and 14 as thromboxane synthase inhibitors. However, the inhibition of platelet aggregation induced by U46619 and of the first wave of ADP-induced aggregation, which is not normally observed with thromboxane synthase inhibitors, suggests additional mechanisms of action for our compounds. On the basis of structural similarities with compounds described previously, these are possibly related to a phosphodiesterase inhibitory activity.