The inotropic and vasodilatory properties of 4,5-dihydro-6-phenylpyridazin--3(2H)-ones are well documented in literature (1-3). Pyridazinone derivatives like SK&F--93741, its nor-methyl derivative and levosimendan ( Fig. 1) possess a substituted amino group at para-position of 6-phenyl ring and have emerged as potent cardiotonic agents with dual inotropic and vasodilatory properties in higher animals (4-6). These pyridazinone-based cardiotonics have shown good promise in the treatment of congestive heart failure; however, species differences in inotropic response to these agents have been observed (7). It is also evident from literature reports that the most dramatic alterations in the potency of pyridazinone based cardiotonics result from varying para-substituents of the phenyl ring attached to 4-position of pyridazinone nucleus. However, position 2 of the pyridazinone ring remains relatively unexplored. Pyridazin-3(2H)-ones further drew our attention because of their easy functionalization at various ring positions (1), which makes them attractive synthetic building blocks for designing and development of novel pyridazinone based cardiotonic agents. The present study describes the synthesis and pharmacological evaluation of 2-substituted-6-(4-acylaminophenyl)-4,5-dihydropyridazin-3(2H)-ones as potent inodilating agents. The synthesis of target compounds 2-4 and 7-11 was achieved by Friedel-Crafts acylation of appropriate anilide derivative with succinic anhydride or methylsuccinic anhydride and subsequent cyclization of intermediary keto acids with various hydrazine derivatives. The newly synthesized pyridazinone derivatives were evaluated for cardiotonic activity using isolated rat atria and for vasorelaxant activity using descending thoracic aortic rings of Wistar rats precontracted with phenylephrine (10 -6 mol L -1 ). 6-(4-Methanesulfonamidophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one (7) exhibited significant inodilatory properties and showed vasorelaxant activity in a nanomolar range (IC 50 = 0.08 ± 0.01 mmol L -1 ).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.