Design, synthesis, and structure-activity relationships of a novel series of 5-alkylidenepyridazin-3(2H)-ones with a non-cAMP-based antiplatelet activity

5-alkylidenepyridazin-3-ones with four points of diversity (R2, R6, X, Y) have been synthesized and evaluated as platelet aggregation inhibitors. Several derivatives eliciting antiplatelet activity in the low micromolar range (e.g., 14e, 14k, 14p, 14v, IC50 congruent with 1 microM) were identified. Structure-activity relationships studies on these compounds revealed the key molecular determinants of this new family of antiplatelet agents: (a) two ester groups in the alkoxy moieties; (b) lipophilic substituents at the N2 position of the pyridazin-3-one. The preliminary results of a pharmacological study aimed at determining the mechanism of action of a set of representative compounds revealed that, unlike Other pyridazinones, the documented antiplatelet effect is not a consequence of a PDE-III inhibitory activity.