Omecamtiv mecarbil

Omecamtiv mecarbil (CK-1827452) is the first potent cardiac myosin activator that can specifically activate the cardiac myosin S1 domain but not other muscle myosins. In clinical trials, omecamtiv mecarbil has been considered as a promising therapeutic approach to treat systolic heart failure¹.

Omecamtiv mecarbil accelerates the actin-dependent P_i release from cardiac myosin S1 domain, thus increases the rate of transition from weakly actin-bound state to strongly actin-bound state (EC₅₀= 2.3 μM)¹.

At the concentration of 200nM, omecamtiv mecarbil was reported to remarkably increase the contractility of adult rat cardiac myocytes without influencing calcium transient. In vivo, Omecamtiv mecarbil has been shown to improve cardiac function without changing myocardial oxygen consumption in both beagle dogs and Sprague-Dawley rats under isoflurane anesthesia¹.

References:
1. Malik FI1, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R, Baliga R, Cox DR, Garard M,Godinez G, Kawas R, Kraynack E, Lenzi D, Lu PP, Muci A, Niu C, Qian X, Pierce DW, Pokrovskii M, Suehiro I, Sylvester S, Tochimoto T, Valdez C, Wang W,Katori T, Kass DA, Shen YT, Vatner SF, Morgans DJ. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science. 2011 Mar 18;331(6023):1439-43.

Dose-dependent electrophysiological effects of the myosin activator omecamtiv mecarbil in canine ventricular cardiomyocytes.[Pubmed:27779469]

J Physiol Pharmacol. 2016 Aug;67(4):483-489.

Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion channels. Therefore, the present study was designed to investigate the effects of OM on action potential morphology and the underlying ion currents in isolated canine ventricular myocytes using sharp microelectrodes, conventional patch clamp, and action potential voltage clamp techniques. OM displayed a concentration-dependent action on action potential configuration: 1 muM OM had no effect, while action potential duration and phase-1 repolarization were reduced and the plateau potential was depressed progressively at higher concentrations (10 - 100 muM; P < 0.05 compared to control). Accordingly, OM (10 muM) decreased the density of the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa) and the rapid delayed rectifier K(+) current (IKr), but failed to modify the inward rectifier K(+) current (IK1). It is concluded, that although the therapeutic concentrations of OM are not likely to influence cardiac ion currents significantly, alterations of the major cardiac ion currents can be anticipated at concentrations above those clinically tolerated.

Omecamtiv Mecarbil Enhances the Duty Ratio of Human beta-Cardiac Myosin Resulting in Increased Calcium Sensitivity and Slowed Force Development in Cardiac Muscle.[Pubmed:28082673]

J Biol Chem. 2017 Mar 3;292(9):3768-3778.

The small molecule drug Omecamtiv mecarbil (OM) specifically targets cardiac muscle myosin and is known to enhance cardiac muscle performance, yet its impact on human cardiac myosin motor function is unclear. We expressed and purified human beta-cardiac myosin subfragment 1 (M2beta-S1) containing a C-terminal Avi tag. We demonstrate that the maximum actin-activated ATPase activity of M2beta-S1 is slowed more than 4-fold in the presence of OM, whereas the actin concentration required for half-maximal ATPase was reduced dramatically (30-fold). We find OM does not change the overall actin affinity. Transient kinetic experiments suggest that there are two kinetic pathways in the presence of OM. The dominant pathway results in a slow transition between actomyosin.ADP states and increases the time myosin is strongly bound to actin. However, OM also traps a population of myosin heads in a weak actin affinity state with slow product release. We demonstrate that OM can reduce the actin sliding velocity more than 100-fold in the in vitro motility assay. The ionic strength dependence of in vitro motility suggests the inhibition may be at least partially due to drag forces from weakly attached myosin heads. OM causes an increase in duty ratio examined in the motility assay. Experiments with permeabilized human myocardium demonstrate that OM increases calcium sensitivity and slows force development (ktr) in a concentration-dependent manner, whereas the maximally activated force is unchanged. We propose that OM increases the myosin duty ratio, which results in enhanced calcium sensitivity but slower force development in human myocardium.

Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction.[Pubmed:28315072]

Handb Exp Pharmacol. 2017;243:465-490.

Myosin is the indispensable molecular motor that utilizes chemical energy to produce force for contraction within the cardiac myocyte. Myosin activity is gated by intracellular calcium levels which are regulated by multiple upstream signaling cascades that can be altered for clinical utility using inotropic medications. In contrast to clinically available cardiac inotropes, Omecamtiv mecarbil is a novel direct myosin activator developed to augment left ventricular systolic function without the undesirable secondary effects of altered calcium homeostasis. Its identification and synthesis followed high-throughput screening of a reconstituted sarcomere, deliberate optimization, exquisite biochemical evaluation, and subsequently promising effects in animal models were demonstrated. Physiologically, it prolonged the duration of left ventricular systole in animal models, healthy adults, and patients with heart failure with reduced ejection fraction (HFrEF) without changing the velocity of pressure development, as assessed in animal models. It has been formulated for both intravenous and oral administration, and in both acute and chronic settings produced similar alterations in the duration of systole associated with beneficial increases in cardiac output, improvements in left ventricular volumes, and reductions in heart rate and often of natriuretic peptides. Small, asymptomatic increases in troponin were also observed in the absence of clinically evident ischemia. Clinically, the question remains as to whether the possible harm of this minimal troponin release is outweighed by the potential benefits of reduced neurohormonal activation, increased stroke volume and cardiac output, and improved ventricular remodeling in patients treated with Omecamtiv mecarbil. The resolution of this question is being addressed by a phase III outcomes trial of this potential novel therapy for heart failure.