Fig4: Structure of CK-1827452

Mentions: The previous candidate compounds provided essential experience for the development of the cardiac myosin activator, CK-1827452 (Fig. 4). CK-1827452 increases cardiac myosin ATPase activity in a dose-dependent manner that is selective for cardiac myosin versus non-cardiac myosins and is independent of the sarcomeric regulatory proteins. As seen with previous myosin activators, CK-1827452 accelerates productive phosphate release (actin-dependent Pi release; Fig. 1, Step 4), increasing the transition from the weak to the strong binding state, while inhibiting non-productive phosphate release (actin-independent phosphate release), hence reducing wasted ATP hydrolysis [18, 19]. In cellular preparations, this compound markedly increased myocyte contraction with an associated increase in the time-to-peak contraction, indicating an increased duration of contraction. This finding is a hallmark of these agents where contraction velocity is largely unaltered, but the time spent contracting is increased. Despite these increases in contractility, there are no changes in the calcium transient and there is no alteration of the sarcoplasmic reticulum calcium content or in the sodium calcium exchanger [20]. CK-1827452 was also able to overcome the inhibition of cross-bridge formation by BDM without increasing the calcium transient magnitude and had no evidence of phosphodiesterase activity [21]. All of these studies confirmed that the mechanism of action of CK-1827452 as a specific cardiac myosin activator, but additional studies in animals demonstrated its potential clinical efficacy.Fig. 4

Teerlink JR - Heart Fail Rev (2009)

Bottom Line: Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency.A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output.These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure.

Affiliation: University of California, San Francisco, USA. john.teerlink@ucsf.edu

Abstract: Decreased systolic function is a central factor in the pathogenesis of heart failure, yet there are no safe medical therapies to improve cardiac function in patients. Currently available inotropes, such as dobutamine and milrinone, increase cardiac contractility at the expense of increased intracellular concentrations of calcium and cAMP, contributing to increased heart rate, hypotension, arrhythmias, and mortality. These adverse effects are inextricably linked to their inotropic mechanism of action. A new class of pharmacologic agents, cardiac myosin activators, directly targets the kinetics of the myosin head. In vitro studies have demonstrated that these agents increase the rate of effective myosin cross-bridge formation, increasing the duration and amount of myocyte contraction, and inhibit non-productive consumption of ATP, potentially improving myocyte energy utilization, with no effect on intracellular calcium or cAMP. Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency. A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output. These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure. A program of clinical studies are being planned to test whether CK-1827452 will fulfill that promise.