A novel class of cardiotonics. Synthesis and pharmacological properties of [4-(substituted-amino)phenyl]pyridazinones and related derivatives

Abstract

A series of [4-(substituted-amino)phenyl]pyridazinones and [4-[(substituted-methyl)amino]phenyl]pyridazinones was synthesized and evaluated for inotropic activity in vitro and for cardiohemodynamic effects in vivo [dogs]. Above all, 6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (4, MCI-154) and 6-[4-(4-pyridylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hydrochloride (5) showed extremely potent positive inotropic activity along with vasodilating activity. Regarding dP/dtmax (an indicator for cardiac contractility), ED30''s (doses that increased dP/dtmax by 30%) of compounds 4 and 5 were 8.5 .+-. 1.9 and 4.4 .+-. 0.6 .mu.g/kg, respectively, where that of amrinone was 471.9 .+-. 94.1 .mu.g/kg. Structure-activity relationships of these series are presented, and a plausible model of receptor binding is discussed.