SCH00013 is a novel Ca2+ sensitizer that elicits a positive inotropic effect without increasing heart rate, prolongs survival in animal models, and demonstrates high oral bioavailability.
SCH00013 is a novel Ca2+ sensitizer that demonstrates positive inotropic effects without increasing heart rate or significantly impairing diastolic function in preclinical models, suggesting potential utility for congestive heart failure.
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 Ca 2+ 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. Ca 2+ sensitizers that act by increasing in myofilament Ca 2+ sensitivity may be able to overcome the disadvantage of Ca 2+ mobilizers. Ca 2+ sensitizers do not increase activation energy, do not produce Ca 2+ 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 Ca 2+ sensitizer that elicits a moderate positive inotropic effect without significant alteration of Ca 2+ 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. SUMMARY The positive inotropic effect of Ca 2+ sensitizers may not be associated with excessive energy consumption of the heart or the Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 on in vitro and in vivo experimental 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.
Endoh et al. (Sat,) conducted a review in Congestive heart failure. SCH00013 vs. EMD 57033 was evaluated. SCH00013 is a novel Ca2+ sensitizer that elicits a positive inotropic effect without increasing heart rate, prolongs survival in animal models, and demonstrates high oral bioavailability.
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