Pharmacology of SCH00013: a novel Ca2+ sensitizer

Abstract

Cardiotonic agents that facilitate cardiac pump function by direct improvement of contractile dysfunction are indispensable for the treatment of hemodynamic disorders in acute myocardial failure and the aggravating phase of congestive heart failure. Cardiotonic agents currently available for the treatment of hemodynamic crisis in congestive heart failure are catecholamines, selective phosphodiesterase (PDE) III inhibitors and digitalis, all of which are Ca2+ mobilizers. Considering the number of serious adverse effects of these clinically available cardiotonic agents, development of agents that act via a novel mechanism of action may contribute to the progress of pharmacotherapy of congestive heart failure. Ca2+ sensitizers that act by increasing in myofilament Ca2+ sensitivity may be able to overcome the disadvantage of Ca2+ mobilizers. Ca2+ sensitizers do not increase activation energy, do not produce Ca2+ overload and may be effective even under pathophysiological states such as acidosis, myocardial stunning and heart failure. SCH00013 ((4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6-tetrahydropyrido-4-yl]pyridazin-3(2H)-one)) is a novel Ca2+ sensitizer that elicits a moderate positive inotropic effect without significant alteration of Ca2+ transients. SCH00013 does not have a positive chronotropic effect and has a weak PDE III inhibitory action and class III antiarrhythmic action. SCH00013 prolonged the survival in a animal heart failure model with genetic cardiomyopathy. The oral bioavailability of SCH00013 is high and equivalent to that via intravenous administration. The unique pharmacological profiles of SCH00013 imply that this agent may be potentially beneficial for pharmacotherapy of contractile dysfunction in congestive heart failure.