New antiplatelet and vasorelaxant agents based on the pyridazinone moiety (1054.6)

Abstract

The pharmacological profile of pyridazinone derivatives includes interesting properties on cardiovascular system as platelet aggregation inhibition and antihypertensive activity. The presence of a 6‐aryl group in the pyridazinone ring was considered essential for the activity on cardiovascular system through the inhibition of phosphodiesterase III (PDE III). Recently, the removal / replacement of the aryl group at C6 has provided potent antiplatelet analogues whose activity does not rely on PDE III inhibition. Therefore, in the search of new structural modifications on the pyridazinone ring that could provide derivatives with novel mechanisms of action, we have designed and synthesized pyridazinones with a functionalized alkyl chain at C4, C5 and/or C6 as well as N2 substituted. Vasorelaxant activity was tested on noradrenaline treated intact rat aortic rings showing several derivatives moderate activity. The most promise results were obtained in the platelet aggregation studies performed following the Born's turbidimetric method and inducing aggregation with thrombine and collagen. Thus, the majority of the new analogues selectively inhibited aggregation induced by collagen in the µM range, being more potent than aspirinGrant Funding Source: Supported by Xunta de Galicia (CN 2012/184)