In Vitro and In Vivo Characterization of CK-1827452, a Selective Cardiac Myosin Activator

Abstract

Current inotropic therapies improve contractility by activating the adenylyl cyclase pathway, by delaying cAMP degradation through inhibition of phosphodiesterase (PDE), or by inhibiting the Na/K exchanger, all of which converge on a final common pathway of increasing the intracellular calcium transient of the cardiac myocyte. However, these calcium dependent treatments can be detrimental to patients with heart failure (HF). A calcium independent approach, increasing cardiac contractility by directly activating cardiac myosin, may address the liabilities of the current inotropic agents. Biochemical specificity, cellular mechanism of action, and in vivo cardiac function in Sprague Dawley (SD) rats, SD rats with HF, and anesthetized dogs was determined with the myosin activator CK-1827452. Biochemical assays demonstrate that CK-1827452 activates the ATPase of an intact cardiac sarcomere by directly activating cardiac myosin. In isolated left ventricular myocytes, CK-1827452 (0.2 μM) increased myocyte contractility without altering the calcium transient. Combination of CK-1827452 with isoproterenol (β-adrenergic agonist) resulted only in an additive increase in contractility with no further change in the calcium transient unlike cAMP dependent inotropic mechanisms. CK-1827452 does not inhibit PDE Type III isolated from human platelets. In vivo contractile function in anesthetized SD rats and dogs was quantitated using echocardiography (M-mode), and simultaneous pressure measurements. CK-1827452 infusion in SD rats (0.25 - 2.5 mg/kg/hr) or dogs (0.03 - 1.0 mg/kg/hr) significantly increased fractional shortening (FS) in a dose-dependent manner with no significant change in peripheral blood pressure or heart rate. Rats with defined heart failure induced by left coronary ligation, or sham treated animals had similar and significant increases in FS when treated with CK-1827452. In summary, CK-1827452 is a cardiac specific myosin activator which increases myocyte contractility without changing the calcium transient, increases FS in rats and dogs, and is efficacious in a rat model of HF. These data indicate that CK-1827452 may be a useful therapeutic in the treatment of human heart failure.