Pharmacology of SCH00013: a novel Ca2+ sensitizer.

M. Endoh, H. Sugawara, M. Mineshima
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引用次数: 8

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.
SCH00013的药理学:一种新的Ca2+敏化剂。
通过直接改善收缩功能障碍促进心脏泵功能的强心剂对于急性心肌衰竭和充血性心力衰竭加重期血流动力学障碍的治疗是必不可少的。目前可用于治疗充血性心力衰竭血流动力学危象的强心剂有儿茶酚胺、选择性磷酸二酯酶(PDE) III抑制剂和洋地黄,它们都是Ca2+动员剂。考虑到这些临床可用的强心剂的严重不良反应,通过一种新的作用机制发挥作用的药物的开发可能有助于充血性心力衰竭药物治疗的进展。Ca2+增敏剂通过增加肌丝Ca2+敏感性的作用可能能够克服Ca2+动员剂的缺点。Ca2+敏化剂不增加活化能,不产生Ca2+超载,即使在酸中毒、心肌昏迷和心力衰竭等病理生理状态下也可能有效。SCH00013((4,5-二氢-6-[1-[2-羟基-2-(4-氰苯基)乙基]-1,2,5,6-四氢吡啶-4-基]吡啶嗪-3(2H)- 1))是一种新型的Ca2+敏化剂,可引起中度正性肌力性作用,而不会显著改变Ca2+瞬态。SCH00013无正性变时作用,具有弱PDE III抑制作用和III类抗心律失常作用。SCH00013延长了遗传性心肌病动物心力衰竭模型的生存期。SCH00013口服生物利用度高,与静脉给药相当。SCH00013独特的药理学特征表明,该药物可能对充血性心力衰竭的收缩功能障碍的药物治疗有潜在的益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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