The pathophysiology of heart failure consists of myocardial failure and the consequent systemic response to the failing myocardium that ultimately leads to peripheral congestion and edema, with the fundamental defect being an impairment of ventricular function resulting in inadequate output to meet the body's metabolic and circulatory demands. Current therapies for positive inotropic support in the U.S. include cardiac glycosides (orally effective but limited by arrhythmogenic liability) and sympathomimetic agents (dobutamine, dopamine; limited by chronotropic liability and oral ineffectiveness). The lack of safe, orally effective positive inotropic agents stimulated the development of new nonsympathomimetic cardiotonics. This paper reports two new potent positive inotropic agents for congestive heart failure: 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H) pyridazinone (1, CI-914) and 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone (2, CI-930). Synthesized from the corresponding 4-(1H-imidazol-1-yl)-γ-oxobenzenebutanoic acids via reaction with hydrazine, these compounds exhibited significant positive inotropic activity in acutely instrumented anesthetized dogs (intravenous administration) and chronically instrumented conscious dogs (oral administration), with 2 showing higher potency. Mechanistic studies revealed they are selective inhibitors of guinea pig cardiac phosphodiesterase fraction III (PDE III), with IC50 values of 8.0 μM (1) and 0.6 μM (2), and in vivo positive inotropic potency correlated with PDE III inhibition. Molecular modeling identified a five-point structural model for positive inotropic activity. Conclusion: 1 and 2 are new potent members of a class of 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones, with 2 being the most potent nonsympathomimetic, noncardiac glycoside cardiotonic agent reported to date. Their positive inotropic effect primarily involves PDE III inhibition, and a structural model rationalizes the key features required for activity in this class of selective cAMP-PDE inhibitors.