Pharmacology of SCH00013: A Novel Ca2+Sensitizer
Authors: Endoh Masao , Sugawara Hiromi , Mineshima Masahiro 
Published: August 2010

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 car‐diomyopathy. 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.

The positive inotropic effect of Ca2+sensitizers may not be associated with excessive energy consumption of the heart or the Ca2+overload that may often exacerbate myocardial dysfunction and provoke lethal arrhythmias during long‐term administration. SCH00013 elicits a positive inotropic effect mainly through an increase in myofilament Ca2+sensitivity without increasing the heart rate. Lack of a positive chronotropic effect may be an important benefit because tachycardia causes an excessive energy consumption and drives the negative force‐frequency relationship in severe CHF patients. In addition, SCH00013 possesses class III antiarrhythmic action. While the major potential disadvantage of Ca2+sensitizers is postulated to be aggravation of the diastolic dysfunction in a failing heart, the effect of SCH00013 on diastolic function was much less than that induced by EMD 57033 in rabbit ventricular myocytes. SCH00013 had little effect on the rate of cardiac relaxation, an indication that the aggravation of diastolic dysfunction may not be a serious complication compared with other Ca2+sensitizers such as EMD 57033. SCH00013 has a high oral bioavailability in dogs and a high safety margin in rats. It does not induce mutagenic effects onin vitroandin vivoexperimental setups. These pharmaco‐dynamic and pharmacokinetic profiles of SCH00013 indicate that the compound possesses highly promising pharmacological characteristics suitable for the treatment of CHF patients in the clinical setting.