Preclinical Research & Development, Cytokinetics, Inc., South San Francisco, CA 94080, USA.
J Mol Cell Cardiol. 2011 Oct;51(4):454-61. doi: 10.1016/j.yjmcc.2011.05.006. Epub 2011 May 17.
Decreased cardiac contractility is a central feature of systolic heart failure and yet we have no effective drugs to improve cardiac contractility. Existing drugs that increase cardiac contractility do so indirectly through signaling cascades and their use is limited by their mechanism-related adverse effects. Direct activation of the cardiac sarcomere to increase cardiac contractility may provide a means to avoid these limitations. Using a reconstituted version of the cardiac sarcomere, we screened a small molecule library and identified several chemical classes that directly activate cardiac myosin. One compound class has been optimized extensively using an iterative process; omecamtiv mecarbil, a small-molecule, selective, cardiac myosin activator is the most advanced exemplar of this novel mechanistic class. It accelerates the transition of myosin into the force-generating state without affecting cardiac myocyte calcium homeostasis. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Initial clinical studies have demonstrated the translation of this mechanism into humans, and further clinical studies of its use in acute and chronic heart failure are planned. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
心肌收缩力降低是收缩性心力衰竭的一个核心特征，但我们目前尚无有效的药物来改善心肌收缩力。现有的能增加心肌收缩力的药物是通过信号级联间接起作用的，其应用受到与其作用机制相关的不良反应的限制。直接激活心肌肌节以增加心肌收缩力可能提供一种避免这些限制的方法。我们使用心肌肌节的重组版本筛选了小分子文库，并鉴定出了几类能直接激活心肌肌球蛋白的化学物质。一类化合物已经使用迭代过程进行了广泛的优化；omecamtiv mecarbil 是一种小分子、选择性的心肌肌球蛋白激活剂，是这一新型机制类别中最先进的范例。它通过增加肌球蛋白进入产生力的状态的速度而不影响心肌细胞钙稳态来加速其转变。在动物模型中，omecamtiv mecarbil 通过增加射血时间而不改变收缩速度来增加心功能。初步的临床研究已经证明了这种机制在人类中的转化，并且计划进一步研究其在急性和慢性心力衰竭中的应用。心肌肌球蛋白激活可能为收缩性心力衰竭提供一种新的治疗方法。本文是题为“肥大和心力衰竭中的关键信号分子”的特刊的一部分。
