Send Orders for Reprints to [email protected] 1 Current Medicinal Chemistry, 2018, 25, 000-000 REVIEW ARTICLE Omecamtiv Mecarbil: A Myosin Motor Activator Agent with Promis- ing Clinical Performance and New in vitro Results Péter Nánási Jr.1, István Komáromi2, Marta Gaburjakova3 and János Almássy4,* 1Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hun- gary; 2Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 3Institute of Molecular Physiology and Genetics, Centre of Bio- sciences, Slovak Academy of Sciences, Bratislava, Slovak Republic; 4Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Abstract: Background: Clinical treatment of heart failure is still suffering from limited efficacy and unfavorable side effects. The recently developed group of agents, the myosin motor activa- tors, act directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. The lead molecule, omecamtiv mecarbil is now in human 3 stage. In addition to the promising clinical data published so far, there are new in vitro results indicating that the ef- fect of omecamtiv mecarbil on contractility is rate-dependent. Furthermore, omecamtiv mecarbil was shown to activate cardiac ryanodine receptors, an effect that may carry proarrhythmic risk. A R T I C L E H I S T O R Y Methods: These new results, together with the controversial effects of the drug on cardiac oxy- Received: May 18, 2017 gen consumption, are critically discussed in this review in light of the current literature on ome- Revised: September 26, 2017 Accepted: November 29, 2017 camtiv mecarbil. DOI: Results: In therapeutically relevant concentrations the beneficial inotropic effect of the agent is 10.2174/0929867325666171222164320 not likely affected by these new results - in accordance with the good clinical data. At su- pratherapeutic concentrations, however, activation of cardiac ryanodine receptors may increase arrhythmia propensity, and the stronger effect on diastolic than systolic cell shortening, ob- served at higher pacing frequencies, may decrease or offset the inotropic effect of omecamtiv mecarbil. Conclusion: Further studies with definitely supratherapeutical concentrations of omecamtiv mecarbil should be designed to map the actual risk of these potentially harmful side-effects. Keywords: Heart failure, inotropic agents, myosin activators, Omecamtiv mecarbil, Ryanodine receptor, Cytosolic Ca2+. 1. INTRODUCTION concomitant Ca2+ overload, resulting in delayed after- depolarizations [1-3]. Furthermore, the incidence of The principles of therapy of heart failure are con- early afterdepolarizations is also increased by - tinuously changing, since all conventional positive β receptor agonists and phosphodiesterase inhibitors due inotropic strategies, including the application of cardiac to the inward shift in transmembrane ion currents in glycosides, β-adrenergic agonists, phosphodiesterase 2+ response to elevated cAMP levels [4, 5]. Another inhibitors, ryanodine receptor stabilizers and Ca sen- common unfavorable effect of -adrenergic agonists sitizers, are burdened by more or less serious side- β and phosphodiesterase inhibitors is the increased oxy- effects. Some of these agents, like cardiac glycosides, gen demand of cardiac muscle, largely ascribed to the β-adrenergic agonists and phosphodiesterase inhibitors, increased rate of Ca2+ cycling, further damaging the are strongly proarrhythmic - partially because of the poor metabolic conditions of the failing heart [6]. The concept of stabilization of cardiac ryanodine receptors *Address correspondence to this author at the Department of Physi- ology, University of Debrecen, H-4012 Debrecen, Hungary; (RyR-2) is based on the pathologic leakiness of RyR-2 2+ Tel: +36-52255575; Fax: +36-52255116; leading to diastolic Ca leak from the sarcoplasmic E-mail: [email protected] reticulum (SR) [7, 8]. This may strongly compromise 0929-8673/18 $58.00+.00 © 2018 Bentham Science Publishers 2 Current Medicinal Chemistry, 2018, Vol. 25, No. 15 Nánási Jr. et al. the pump function of the heart due to the increased dia- dine-3-yl) carbamoyl]amino}phenyl)methyl] pipera- stolic Ca2+ level combined with the reduced Ca2+ con- zine-1 -carboxylate), known also as CK-1827452. tent of the SR, resulting in diastolic and systolic failure, The first structure reported to enhance the ATPase respectively. Ryanodine receptor stabilizers, such as activity of myosin was CK-0156636. Water solubility Rycal, K201 and JTV519, improve the contractile per- was improved and protein binding was reduced by sub- formance by reducing diastolic Ca2+ leakage and de- stitution of the nitrate group for fluorine in the succes- crease the energy demand of cardiac muscle [9, 10]. sor, CK-1032100. The first agent found to increase Here, it should be mentioned that the opposite strategy, fractional shortening of cardiac muscle was CK- i.e. pharmacological activation of RyR-2, has also been 1122534, but its selectivity was insufficient due to in- suggested to treat heart failure. teractions with ATP-sensitive K+ channels. In the next An alternative way to support cardiac contractility is step CK-1213296 was developed. This compound to enhance the efficacy of the Ca2+ signal. In this case failed to interfere with cardiac ion channels but sup- less Ca2+ is required to generate a given tension, conse- pressed the activity of CYP 1A2. All these unfavorable quently less energy has to be wasted for accumulation effects were eliminated from CK-1317138, while the of Ca2+ into internal stores or pumping it out of the cell optimal effects were obtained with omecamtiv mecarbil [11]. Ca2+ sensitizer drugs improve the mechanical per- (CK-1827452), which was more effective than its an- formance of cardiac muscle by increasing the affinity cestor, by one order of magnitude [20, 21]. The chemi- of troponin C to Ca2+ without increasing substantially cal structures of these compounds, including omecam- the oxygen consumption of the heart [12, 13]. In ab- tiv mecarbil, are presented in Fig. (1), where the men- sence of increased Ca2+ cycling, elevated arrhythmia tioned structural modifications are indicated by circles. incidence is not anticipated with these agents [14]. The The positive inotropic effect of omecamtiv mecarbil 2+ most serious side-effect of Ca sensitizers is diastolic is based on its selective association to the S1 domain of stiffness manifested in compromised ventricular filling the heavy chain of cardiac β-myosin at the site where as a consequence of hampered relaxation of myocar- the converter domain and the relay helix converge in dium. From this (and only this) point of view, the the vicinity of the force-generating lever arm. The con- 2+ phosphodiesterase inhibitory action of some Ca sensi- secutive conformational change in the nucleotide- tizers, like levosimendan or pimobendan, may be binding domain of myosin results in enhanced ATPase beneficial [11, 15]. activity and also in robust alterations of the mechanical properties of myosin head [21]. Due to the allosteric 2. CONCEPT OF MYOSIN ACTIVATION: OME- modulation of the nucleotide-binding domain, the inor- CAMTIV MECARBIL AND ITS MECHANISM ganic phosphate production, which is the rate-limiting OF ACTION step of the actomyosin cycle, is accelerated by ome- The ideal inotropic agent (1) should enhance cardiac camtiv mecarbil. As a consequence, the transition rate pumping selectively without altering other parameters between the weakly bound and the strongly bound con- of cardiac function, (2) should not increase substan- figurations of the actin-myosin dimer also accelerates tially cardiac energy consumption, and (3) should not [22]. The resultant higher number of force-generating increase the incidence of cardiac arrhythmias [16]. cross-bridges increases the amplitude and lengthens the Since these requirements can hardly be met with inter- duration of contractions [22-26]. Indeed, in vitro mo- actions upstream to the contractile machinery, the bility assay experiments, performed with porcine and downstream steps came into the focus of the research. human myosins, revealed that omecamtiv mecarbil re- The term “positive inotropy with a downstream duced unloaded shortening velocity in accordance with mechanism of action” represents an alternative ap- stabilization of the “strongly bound” configuration of proach of “Ca2+ sensitization”, when Ca2+ binding af- myosin heads [27-29]. finity of troponin C in not altered; in contrast, the en- The ATPase stimulant effect of omecamtiv mecarbil hancement of the systolic force is achieved by direct is restricted exclusively to α and β myosin isoforms modification of the actin-myosin cycle [14, 17-19]. obtained from cardiac and slow skeletal muscles, inde- 2+ Myosin motor activator agents differ from Ca sensi- pendently of the origin of the thin filament. Myosins tizers, since they increase cardiac contractility by bind- from fast skeletal or smooth muscles are not affected, ing to the heavy chain of the cardiac myosin molecule, but slow skeletal muscles are somewhat sensitive to the as the selective cardiac myosin activator, omecamtiv drug. Accordingly, omecamtiv mecarbil can display mecarbil (methyl 4-[(2-fluoro-3-{[N-(6-methylpyri- marked effects in healthy (containing both α and β Myosin Motor Activators Current Medicinal Chemistry, 2018, Vol. 25, No. 15 3