Recent Advances in Novel Modulators for Cardiac Myosin Disorders

Abstract

In advanced stages of heart disease, most cases are characterized by heart failure, where the heart's systolic and diastolic functions are weakened, and then it cannot meet the body's normal oxygen demands. The contraction of the heart, at the molecular level, involves the interaction between thick filaments (primarily composed of myosin) and thin filaments (primarily composed of actin), where adenosine triphosphate is used as an energy source to generate contraction force. In view of this, cardiac myosin may be a crucial target for the regulation of heart-related diseases. In 2022, mavacamten was approved by the Food and Drug Administration as a first-in-class myosin modulator for the treatment of obstructive hypertrophic cardiomyopathy. At the same time, there is continuing evidence that indicates cardiac myosin modulators as potential agents for the treatment of a variety of cardiac conditions. This review summarizes the current discovery, design, and indication of cardiac myosin modulators to provide valuable insights for further drug development in related fields.

 

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Keywords

obstructive hypertrophic cardiomyopathy - mavacamten - cardiac myosin modulators

Introduction

The heart is a complex organ composed of cardiac muscle cells and various other cell types, including endothelial cells, vascular smooth muscle cells, fibroblasts, pericytes, and immune-related cells. Cardiac muscle cells are responsible for the contraction of the heart, allowing the blood to be pumped.[1] [2] The sarcomere, the basic contractile unit of myocytes, is a unique specialization of the actin cytoskeleton found in higher organisms.[3] [4] Sarcomere is composed of parallel repeating units that consist of myosin-containing thick filaments, actin-containing thin filaments, and stabilizing thin filaments.[4] All of these are laterally surrounded by Z-discs containing actin, which are cross-linked to the cytoskeleton by actinin. The region adjacent to the Z-disc is called the I-band, which consists of the thick filaments of the entire length. Within the A-band is a region where thin filaments do not overlap, called the H-zone, containing the myosin-rich M-line corresponding to the center of the sarcomere ([Fig. 1]).[4] [5] In reaction to intracellular calcium levels, the troponin regulatory complex, located on the thin filament, undergoes a sequence of structural changes that expose myosin-binding sites on actin, allowing myosin head to attach to actin and initiate twitch contraction via adenosine triphosphate (ATP)-utilizing power stroke. This action brings the Z-disc nearer to the M-line, thereby shortening the sarcomere.[5] The precise architecture and molecular coordination of sarcomeres are essential for maintaining cardiac contractility, and any impairment of function will lay the foundation for cardiovascular diseases (CDVs) that threaten life.

Fig. 1 The structure of sarcomere.

According to the World Health Organization, CDVs continue to be the leading cause of death among noncommunicable diseases globally, with approximately 19.7 million people dying from CDVs in 2019.[6] CDVs include conditions such as coronary artery disease, rheumatic heart disease, and cardiomyopathy. In the advanced stages of many cardiovascular disorders, patients often develop heart failure, which is one of the most pressing public health challenges, affecting millions of adults worldwide.[1] [7] Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases, and its incidence and prevalence are increasing due to the aging population and rising rates of metabolic diseases such as obesity, diabetes, and hypertension.[8]

Diastolic dysfunction is central to the HFpEF pathophysiology, arising from multifactorial cardiac, vascular, and systemic abnormalities. Similar functional impairments are also observed in hypertrophic cardiomyopathy (HCM), which is a genetic disorder marked by left ventricular wall thickening and stiffness, disrupting both diastolic and systolic functions and ultimately impairing cardiac output.[9] Although HFpEF and HCM arise from distinct etiologies, they converge on dysregulation of sarcomeric contractile machinery as a shared pathological mechanism, thereby offering a common therapeutic target. Evidence suggested that myosin modulators can rebalance contractility, offering the potential to halt or reverse disease progression in both conditions.[9] [10] This propelled the development of targeted therapies focusing on myosin, the molecular motor of sarcomeres. In April 2022, the Food and Drug Administration (FDA) approved mavacamten, the first cardiac myosin inhibitor (CMI) for obstructive HCM (oHCM), which is a landmark advancement. Clinical trials have demonstrated its robust biochemical activity, in vitro and in vivo efficacy, and an acceptable safety profile for oHCM patients.[11] [12]

Building on this success, another myosin inhibitor, aficamten, has entered clinical evaluation. Parallel studies have explored the opposite therapeutic strategy of enhancing contractility in heart failure with reduced ejection fraction (HFrEF) through myosin activation.[13] Promising candidates include omecamtiv mecarbil and danicamtiv, both of which are advancing in clinical trials ([Table 1]). Collectively, these developments underscore the emergence of myosin modulators as a transformative therapeutic class, with growing potential to address diverse cardiac pathologies. This review synthesizes their discovery, molecular design, and clinical applications, emphasizing their evolving role in cardiac disease management, to provide reference and inspiration for the development of new drugs in this field.

Table 1 Overview of myosin modulators targeting cardiac muscle

Name	Structure (derivatives)	Mechanism of action	Highest R&D status	Condition
Mavacamtten		Cardiac myosin Inhibitor	Approved for listing	Hypertrophic cardiomyopathy; heart failure with preserved ejection fraction
Omecamtiv Mecarbil		Cardiac myosin Activator	Apply for listing	Acute heart failure; angina pectoris; chronic heart failure
Aficamten		Cardiac myosin Inhibitor	Apply for listing	Hypertrophic cardiomyopathy
Danicamtiv		Cardiac myosin Activator	Clinical phase I	Heart failure with reduced ejection fraction; cardiomyopathy, dilated (congestive)
Ulacamten		Cardiac myosin Inhibitor	Clinical phase II	Cardiovascular disorders
EDG-7500	/	Cardiac myosin Inhibitor	Clinical phase II	Hypertrophic cardiomyopathy
Delocamten		Cardiac myosin Inhibitor	Clinical phase II	Hypertrophic cardiomyopathy; heart failure with preserved ejection fraction
Blebbistatin		Cardiac myosin and MYH2 inhibitors	Preclinical	Not determined

 

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Cardiac Myosin Inhibitors and Hypertrophic Cardiomyopathy

The Causes of Hypertrophic Cardiomyopathy

HCM is a prevalent autosomal dominant genetic heart muscle disorder that occurs in approximately 1 out of every 500 adults worldwide and stands as a primary cause of sudden cardiac death in young adults.[14] HCM is diagnosed when patients present with left ventricular hypertrophy that cannot be explained by another cardiac or systemic disease.[14] Associated histopathologic findings include enlarged and disorganized cardiomyocytes and increased amounts of myocardial fibrosis. HCM also perturbs heart function, as evidenced by characteristically hyperdynamic contraction and impaired relaxation.[15] [16] [17] The disease originates primarily from mutations in genes encoding cardiac myofibrillar proteins.[11] Dominant inherited and de novo mutations in genes encoding sarcomeric proteins—the contractile unit of the heart—are identified in 35% of unselected patients undergoing genetic testing[18] and 80% of familial HCM cases.[19] The two most frequently mutated HCM genes encode β-cardiac myosin heavy chain (MYH7), the predominant myosin isoform expressed in the adult human heart, and myosin-binding protein C (MYBPC3), a modulator of cardiac contraction.[18] [20] [21] [22] These mutations disrupt the expression of respective proteins, leading to various functional changes within cardiac myofiber cells. These changes include abnormal increases in ATPase activity, irregular formation of cross-bridges with myosin, and alterations in the responsiveness to Ca²⁺ ([Fig. 2]).[23]

Fig. 2 The development of hypertrophic cardiomyopathy.

These molecular perturbations trigger a cascade of biomechanical dysfunction. Specifically, mutant myosin shifts from its energy-saving superrelaxed state to a hyperactive, strongly actin-bound conformation.[20] [24] This sustained hypercontractility triggers three interconnected pathological responses: (1) release of stress-responsive signaling molecules (e.g., prohypertrophic factors); (2) activation of maladaptive pathways that promote hypertrophy, inflammation, and fibrosis;[25] and (3) structural remodeling characterized by myocyte hypertrophy, cellular disarray, and interstitial fibrosis.[26] Collectively, these changes culminate in the hallmark features of HCM: thickened ventricular walls, diastolic impairment, and arrhythmogenic substrate.

To study the role of sarcomere mutations in the development of HCM, Green's team used previously generated mouse models of HCM, which were created by introducing human disease-causing mutations into the murine α-cardiac myosin heavy chain gene.[16] This isoform, which shares 92% sequence homology with the human β-cardiac myosin heavy chain, dominates ventricular expression in adult mice. These models, by introducing heterozygous missense mutations at three critical sites: R403Q (actin-binding domain); R453C (adjacent to nucleotide-binding pocket); and R719W (converter domain), recapitulated hallmark HCM phenotypes, including ventricular hypertrophy, cardiomyocyte disarray, and aberrant contractility.[16]

HCM-associated mutations, at the molecular level, induce gain-of-function biophysical alterations in the myosin motor domain. Biochemical assays using in vitro reconstituted systems and patient-derived myofibrils revealed that mutant myosins have enhanced ATPase activity, increased isometric force generation, and accelerated actin filament sliding velocities.[15] These molecular phenotypes of hypercontractile align with clinical observations of hyperdynamic cardiac contraction. However, in reconstituted systems, some of the HCM mutant proteins do not demonstrate increased power production and appear to slightly decrease the production of force.[27]

To directly test the “excessive sarcomere power output” hypothesis, the team employed a reverse pharmacology strategy to identify small-molecule inhibitors of myosin ATPase activity. Theoretical modeling predicts that selective attenuation of mechanical work output could (1) normalize hypercontractility, (2) suppress mechanoactivated hypertrophic signaling (e.g., >70% inhibition of calcineurin/NFAT pathways), and (3) disrupt fibrotic cascades, thereby achieving multidimensional mitigation of HCM progression. To test this hypothesis in another approach, they sought a small molecule that could reduce sarcomere power output. They reasoned that if sarcomere power excess is the primary defect in HCM, then small-molecule inhibitors of sarcomere power might ameliorate the disease at its source and abolish hallmark features of HCM such as hypertrophy, cellular disarray, and myocardial fibrosis.

 

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Mavacamten

Interestingly, in 2016, Green and colleagues demonstrated that small molecules that inhibit sarcomeres' power output could improve the characteristics of HCM, including hypertrophy, cellular disarray, and myocardial fibrosis,[16] validating the hypothesis mentioned above. They then developed the first-generation CMI, mavacamten, by conducting chemical screening and structural optimization, which was approved in the market for the treatment of oHCM in 2022.[28] Green and colleagues conducted a chemical screen to seek compounds that reduce the maximal actin-activated ATPase rate of myosin in bovine myofibrils, for decreases in the myosin ATPase rate resulted in a less ensemble force generation, which is positively correlated to the power output of sarcomere.[16] This reduction in myosin-ATPase rate leads to an overall decrease in force generation, positively correlated with the power output of sarcomeres. Through the screening process, a series of compounds containing the pyridine-2,4-(1H,3H)-dione core were identified ([Fig. 3]).[16] [29]

Fig. 3 Structure-activity relationship exploration of the pyridine-2,4-(1H,3H)-dione core.

First, the structure modification of these compounds focused on the substituents at R¹ and R² positions. The screening of R¹ substituents revealed that cyclohexyl or cyclohexyl with two fluorine substitutions, as well as methyl or trifluoromethyl-substituted cyclopropyl, exhibited high biochemical activity. In contrast, a simple cyclopropyl or cyclobutyl showed low activity. Those results suggested that the size and structure of the cycloalkyl and related groups are associated with the activity of compounds, and the presence of an oxygen atom in the cycloalkyl group resulted in reduced activity.

Straight-chain or branched alkyl substitutions for R¹ were explored next. It was observed that straight-chain alkyls such as methyl, ethyl, n-propyl, and butyl led to lower activity. However, when the substituent was changed to isopropyl or n-pentyl, the activity was increased, suggesting that the biological activity was higher when R¹ is a branched alkyl group. Similarly, attempts have been made to replace R¹ with aromatic rings, and the result showed that compounds with a substituted six-membered ring have higher activity. However, when the five-membered aromatic heterocycle was introduced, the structure-activity relationship (SAR) was not clearly defined, necessitating further exploration.

Subsequent exploration focused on the substitution of R². The result showed that compounds with phenyl derivatives at R² directly connected to a chiral carbon atom exhibited good activity in most cases. However, when R² was replaced with pyridyl, 4-pyridylmethyl, or benzyl, the compounds demonstrated lower activity against cardiac myosin ATPase. Interestingly, the insertion of another carbon between the chiral carbon atom and the benzyl group increased the inhibitory activity.

In the exploration of R³ and R⁴ substituents, it was found that when R⁴ was a hydrogen atom, the structure of R³ had a certain impact on the biochemical activity of the compounds. When R³ was ethyl, n-propyl, cyclopropyl, cyclobutyl, trifluoromethyl, hydroxymethyl, or methoxymethyl, the compounds exhibited higher biochemical activity against cardiac myosin ATPase. However, the activity decreased when it was substituted with benzyl hydroxymethyl or isopropyl.

Then, the X-substitution was explored. When the bromine atom is substituted at the 5-position of the pyrimidinedione core, the compound exhibits similar activity to that with hydrogen substitution. However, the inhibitory activity against cardiac myosin ATPase is significantly reduced when fluorine or methyl is substituted at this position.

Finally, chiral screening of the compounds was conducted, and it was confirmed through a series of experiments that the configuration of the compound played a crucial role in maintaining the activity of a range of compounds; among them, the S-configuration is better than the R-configuration. Following activity screening, compound 5, also known as mavacamten, was selected as a candidate drug.[29]

Recently, Auguin and colleagues explored the structure of mavacamten-bound bovine β-cardiac myosin and found that the allosteric binding pocket of this inhibitor is also where omecamtiv mecarbil, the activator of contraction, binds. All-atom molecular dynamics simulations explain the origin of their antagonistic effect on myosin allostery. This provides the blueprint of the mechanisms underlying the modulation of myosin activity and regulation through the omecamtiv mecarbil/mavacamten pocket.[30]

Currently patented mavacamten synthetic route is as follows ([Fig. 4]): starting with isopropylamine (1), it undergoes a reaction with trimethylsilyl isocyanate to obtain 1-isopropylurea (2), which reacts with dimethyl malonate to obtain 1-isopropylpyrimi-dine-2,4,6(1H,3H,5H)-trione (3). Then, the compound (3) undergoes chlorination with phosphorus oxychloride and finally reacts with L-1-Phenylethylamine to yield the target product mavacamten (5).[31]

Fig. 4 Mavacamten synthesis.

Mavacamten has demonstrated significant inhibitory effects on cardiac myosin in both in vitro and in vivo experiments. Subsequent Phase II and Phase III clinical trials indicated substantial improvements in patients treated with mavacamten, particularly in terms of left ventricular outflow tract (LVOT) obstruction, functional capacity, and overall health status. Mavacamten is clinically effective and well-tolerated.[10] Its emergence addresses the limitations of traditional medications that only control symptoms without improving cardiac function. Mavacamten has shown a more proactive therapeutic effect and favorable safety profile, effectively slowing disease progression and restoring heart function. This brings new hope for the prognosis of HCM patients.

The mechanism investigation showed that mavacamten can promote the super-relaxed state of myosin by changing the myosin head from an open “ON” state (disordered relaxation state) to a folded closed conformation (IHM, super-relaxed “OFF” state), reducing the binding of the myosin head to actin.[32] [33] At the same time, the myosin ATP turnover rate in the super-relaxed state is significantly reduced, lowering energy consumption. Mavacamten also slows down the rate of Pi release in a concentration-dependent manner (without affecting ADP release), blocking contraction signal transduction activated by actin.[34] [35] As a small molecule directly targeting cardiac myosin, mavacamten reclaimed a brand-new field for the treatment of HCM and new horizons in the understanding of HCM.

Given the success of mavacamten in HCM in improving patients' diastolic function and myocardial energy metabolism,[10] it may also have a certain improvement effect in patients with HFpEF. However, LV global longitudinal strain[36] and contractile reserve[37] are often impaired in HFpEF and may be further worsened by CMIs. Given these potential benefits and the uncertainty about the role of CMIs in HFpEF, the study of mavacamten in participants with HFpEF and chronic elevation of cardiac biomarkers (EMBARK-HFpEF) proof-of-concept trial was designed to explore the potential efficacy and safety of mavacamten in patients with HFpEF and a left ventricular ejection fraction (LVEF) of 60% or greater. The final results show that after 26 weeks of mavacamten treatment, N-terminal pro-brain natriuretic peptide (NTproBNP), high-sensitivity troponin T (hsTnT), high-sensitivitytroponinI (hsTnI) were significantly reduced, and LVEF did not continue to decline.[38] A dose-finding, phase 2 randomized clinical trial of a next-generation CMI (BMS-986435/MYK-224) is currently underway (the AURORA-HFpEF trial [ClinicalTrials.gov Identifier: NCT06122779]) to further validate and expand upon these findings.

 

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Aficamten

However, the first-generation inhibitor mavacamten exhibited certain issues in clinical trial data, including a long half-life in the human body,[39] requiring an extended time to reach the target blood concentration in patients, and affecting the expression of CYP3A4 and CYP2B6.[40] To address these issues, Cytokinetics, Inc. developed the second myosin inhibitor using high-throughput screening (HTS) with bovine cardiac myosin as a measurement for ATP hydrolysis rate, and identified compound 6 ([Fig. 5]) as a lead compound for optimization.[41] [42]

Fig. 5 Structure-activity relationship exploration of aficamten. CL_int, intrinsic clearance in human microsomes.

In the absence of structural information on the binding site, initial optimization attempts were aimed at exploring the position of the dihydroindole N and the effect of the substituents on N on the activity. Bovine cardiac myosin fibers inhibiting assay showed that the 5-indazole isomer, with a phenylacetyl amide substituent on N (compound 7), exhibited better activity.

Through SAR exploration, the compound was demonstrated to interact with cardiac myosin, suggesting a potential shared binding site with known myosin inhibitors such as Blebbistatin. The crystal structures revealed a crucial hydrogen bond between the hydroxyl moiety of Blebbistatin and the main-chain carbonyl (Leu262) of cardiac myosin II. On this basis, the replacement of the indoline core of compound 8 with the 2,3-dihydro-1H-inden-1-amine core of compound 9 allowed the formation of a similar hydrogen bond between compound 9 and the backbone carbonyl (Leu 267) of cardiac myosin. It was also found that the phenyl ring of compound 9 could fit into a similar hydrophobic pocket as the N-phenyl group from the pyrrolidine ring of Blebbistatin, and the oxadiazole of compound 9 could form a hydrogen bond with alanine 463 in cardiac myosin. The potency of compound 9 was approximately 20-fold higher than that of compound 8 (IC₅₀ values of 1.0 and 19.1 μmol/L, respectively), providing a new core structure for optimizing drug-like properties.

The lipophilicity of the compound was reduced to lower its inherent clearance in human microsomes and improve its drug-like properties. The SAR results suggested that replacement of the original benzoyl group with a less lipophilic heterocyclic amide (as determined by the calculated log p-value) reduces microsomal turnover and increases free drug exposure. Stereochemical studies also revealed that the R-configuration was significantly more active than the S-configuration, with better in vitro microsomal and in vivo clearance rates. The final optimized compound 10 was named aficamten (formerly known as CK-3773274 or CK-274), and its patent-reported synthetic route is shown in [Fig. 6].[41] [42]

Fig. 6 Aficamten synthesis.

Aficamten and mavacamten have demonstrated certain effectiveness in clinical trials. Mavacamten is a myosin ATPase allosteric inhibitor that reduces the formation of actin–myosin cross-bridges, thereby decreasing myocardial contractility and improving ventricular compliance. However, aficamten reduces the number of interactions between myosin heads and actin during relaxation, leading to a decrease in contractility and consequently a reduction in the LVOT gradient.[41] [43]

Currently, the clinical Phase I/II study named REDWOOD-HCM of aficamten has completed its investigation. The result of the Phase I study showed that in most oHCM patients, the treatment of aficamten at different doses was associated with a rapid, sustained, and significant reduction in LVOT gradient. Concurrently, improvement was observed in heart failure symptoms and clinically relevant biomarkers.[43] [44] The result of the Phase II study showed that, compared with the placebo, most patients treated with aficamten achieved the treatment goal, i.e., reducing the resting gradient to below 10 mm Hg at week 50 and the Valsalva gradient to below 7 mm Hg (7.0%, p < 0.0001 vs. placebo), with a roughly similar incidence of adverse events among the treatment groups.[45] However, in comparison to mavacamten, aficamten has some potential pharmacokinetic advantages including a shorter half-life (∼7 days vs. mavacamten's 10–12 days), a wider therapeutic window, no interaction with CYP19C3 and CYP4A, and no substantial impact on cytochrome P450, reducing the likelihood of drug interactions ([Table 2]). Based on this, a Phase III clinical trial of aficamten began in September 2023 to evaluate the clinical efficacy and safety of the drug in treating patients with oHCM.[41] [44] [45]

Table 2 Comparison of aficamten and mavacamten[42]

Assay	Aficamten	Mavacamten
Cardiac myofibril IC50 (μmol/L)[a]	1.26 (1.20–1.33)	0.6 (0.54–0.67)
Rat FS IC10 (μmol/L)	0.8	0.6
Rat FS IC50/IC10	9.9	2.8
Human t 1/2 (projected, days)	2.8	9
Human t 1/2 (actual, days)	3.4	7-9
CYP induction EC50 (μmol/L)	No substantial induction up to 25 μmol/L for 3A4, 2B6, and 1A2	2.2 ± 0.4 (3A4) 5.1 ± 0.2 (2B6)
CYP450 inhibition (IC50, μmol/L)[b]	>100	>30
Time-dependent CYP inhibition	None	NA[c]

Abbreviation: FS: fractional shortening.

^a Cytokinetics internal data.

^b Mavacamten was tested in the subtypes of CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5; and afificamten was tested in the subtypes of 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.

^c NA: data not available.

Apart from mavacamten and aficamten, other myosin inhibitors currently in clinical stages include CK-271 (CK-3772271), CT-G20, and CK-586 (CK-4021586) in Phase I, as well as MYK-224 (BMS-986435) in Phase II. However, the structures of these investigational drugs are yet to be disclosed.

 

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Cardiac Myosin Activator and Heart Failure

Heart failure is a common human disease and the most frequent cause of hospitalization in people over 65.[46] Heart failure is a complex clinical syndrome characterized by impaired ventricular filling or ejection, or both, manifesting as dyspnea or exercise intolerance. Once developed, it results in significant morbidity and mortality. Traditionally, heart failure has been categorized into three subtypes based on LVEF: heart failure with preserved ejection fraction (LVEF ≥ 50%), heart failure with mid-range ejection fraction (HFmrEF, LVEF 41-49%), and HFrEF (LVEF ≤ 40%).[47]

For more than a century, scientists have sought treatments to increase cardiac contractility, believing that improving ventricular systolic performance will blunt harmful neurohormonal activation, reverse adverse ventricular remodeling, and improve clinical outcomes.[48] In hypocontractile diseases, therapy to increase cardiac contractility has substantially relied on three types of inotropic agents for a long time[20]: (1) digitalis-derived cardiotropic glycosides, the oldest inotropic drugs, which inhibit the sodium–potassium ATPase pump, leading to the accumulation of Na⁺ that, in turn, reverses the sodium–calcium exchanger and leads to increased Ca²⁺ influx in systole; (2) β-adrenergic agonists including dopamine or dobutamine; and (3) phosphodiesterase inhibitors, which lead to increased levels of cAMP, thereby avoiding desensitization and downregulation of cardiac β-adrenergic receptors. All these agents rely on a generalized disruption of Ca²⁺ homeostasis in cardiomyocytes to increase contractility.[20] [49] [50] [51]

The current cornerstone for guideline-directed medical therapy for HFrEF focuses on the inhibition of the renin–angiotensin–aldosterone and sympathetic nervous systems, combined with neprilysin inhibition to potentiate beneficial pathways.[47] Neprilysin—a neutral endopeptidase that degrades several peptides involved in cardiovascular and renal homeostasis—is pharmacologically targeted to enhance protective neurohormonal signaling. Renin–angiotensin–aldosterone system antagonists, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, reduce HFrEF morbidity and mortality by 20 to 30% in all-cause mortality. However, their use is limited by nondose-dependent dry cough caused by pulmonary bradykinin accumulation, a class effect of all ACE inhibitors.[47]

In this therapeutic landscape, myosin activators have emerged as a novel drug class with a distinct mechanism of action. Unlike traditional inotropes that increase intracellular calcium concentrations, these agents selectively enhance cardiac sarcomere function by stabilizing myosin in the force-generating state, improving mechanical efficiency without increasing oxygen consumption.[52]

 

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Omecamtiv Mecarbil

Cytokinetics, Inc. also developed omecamtiv mecarbil for the treatment of HFrEF. Omecamtiv mecarbil (AMG-423, CK-1827452) is the first drug that selectively binds to cardiac myosin to enhance cardiac contractility. The binding site of omecamtiv mecarbil is located in a pocket between the N-terminus, transducer, relay helix, and converter of myosin. This binding stabilizes the pre-powerstroke state (PPS) state and allows more myosin heads to be in a ready state at the beginning of the cardiac contraction cycle. Once calcium ions trigger contraction, these heads can bind faster to actin and release phosphate (Pi), thereby enhancing contraction force.[52] However, an in vitro motility assay showed that omecamtiv mecarbil inhibits actin gliding,[53] [54] and it affected tension development and relaxation in myocytes and muscle fibers at micromolar concentrations.[54] [55] In response to these findings, Woody et al proposed a stroke-eliminated, prolonged time of attachment model to explain the activation of muscle by omecamtiv mecarbil.[56] The model proposed that long-lived, omecamtiv mecarbil-bound myosins activate the thin filament regulatory system, allowing the omecamtiv mecarbil-free, fully functioning myosin to bind to actin at low calcium concentrations. This results in higher-force myocyte contractions at a given calcium concentration than would be achieved in the absence of omecamtiv mecarbil.[54] [56] In summary, the unique mechanism of omecamtiv mecarbil distinguishes it from traditional positive inotropic drugs, and unlike agents that increase intracellular calcium levels, omecamtiv mecarbil enhances cardiac contractility without causing side effects such as increased myocardial oxygen consumption.[52] [57] [58] [59]

The discovery of omecamtiv mecarbil stemmed from HTS campaigns that identified compound 19 as a cardiac-specific myosin activator. Subsequent iterative structural optimization for pharmacophore stability, binding specificity, and pharmacokinetic properties ultimately made omecamtiv mecarbil a first-in-class therapeutic agent for HFrEF.[57] Compound 19 exhibits excellent selectivity for cardiac sarcomeres against skeletal muscle sarcomeres. Meanwhile, it demonstrates enhanced contractile capability in freshly isolated adult rat cardiac myocytes, with no observed impact on calcium transients in cardiac cells, and was chosen as the lead compound for further study.[57] However, compound 19 exhibited several issues, including the presence of a nitro group, the instability of amide, poor water solubility, low free fraction, moderate intrinsic efficacy, off-target effects (e.g., direct vasodilation through KATP channel activity and CYP 1A2 inhibition), and high intrinsic clearance rate. It is necessary to optimize the structure of this compound to address these problems.

The first step was to remove the nitro group from 19. The original nitro group is an electron-withdrawing group capable of reducing the likelihood of oxidation metabolism of adjacent aromatic rings. When it was replaced with a fluorine atom, the original biological activity of the compound (20, [Fig. 7]) was maintained, while when it was replaced with hydrogen, the activity of the compound was significantly reduced, confirming this point.

Fig. 7 Structure-activity relationship exploration of omecamtiv mecarbil.

The next step was to address the low hydrolytic stability and poor water solubility of the amide moiety. When the amide was replaced with urea, the hydrolytic stability of the compound was improved, with biochemical efficacy maintained, significantly enhancing cardiac cell activity. Additionally, when the C3 portion on the terminal benzene ring was replaced with an N atom and the adjacent F substituent, a pyridine structure was formed (compound 21, [Fig. 7]), which increased the solubility of the compound without affecting biological activity. Subsequent efforts focused on exploring strategies to reduce protein binding, eliminate off-target activities, improve efficacy against cardiac cells, and enhance intrinsic clearance. It was found that the addition of a saturated aromatic ring to the “left” side of the compound, which acts as a hydrogen bond acceptor, proved effective in maintaining activity while reducing protein binding. Comparative studies indicated that the amino ester or N,N-dimethylsulfonamide structures were more effective in this regard.

The microsomal extraction rate (Re) in humans suggested that altering the chirality between the pyridine ring and the benzene moiety improved oxidative metabolism. The inhibitory effect of this compound on CYP 1A2 can be eliminated by spatial blockade, which can be achieved by attaching a methyl group near the pyridine nitrogen on the “right” side (compound 22, [Fig. 7]).

Subsequent optimization was conducted, focused on reducing oxidative turnover to improve in vivo pharmacokinetic parameters, enhance solubility in veins, and increase efficacy against cardiac cells. As shown in [Fig. 7], replacing the left part with a methylenepiperazine ring (23) reduced the microsomal extraction rate, increased solubility significantly, and improved efficacy against cardiac cells. In contrast to the initial SAR revealed that removing the 5-fluorine from the central ring did not weaken potency. However, the reintroduction of fluorine at position 2 of the central ring (24) increased the effect on cardiac cells ([Table 3]), and the introduction of the basic nitrogen of piperidine improved the physical properties of the molecule, with this nitrogen's weak basicity (pK _a = 6.1) introducing no additional off-target interactions. Subsequent experiments in animal models confirmed the feasibility of omecamtiv mecarbil as a drug.[57] [60] Amgen Inc. has also reported the process preparation route for compound 24 ([Fig. 8]).[61]

Fig. 8 Omecamtiv mecarbil synthesis.

Table 3 Additional improvements between compound 23 and 24 [57]

Compound	AC40 (μmol/L)	CM (ΔFS % at μmol/L)	Shake Sol (mg/mL at pH 5)	PB (% bound)
23	1.7	131 at 0.8	4.6	89.7
Omecamtiv mecarbil (24)	0.58	123 at 0.2	2.2	79.6

Abbreviations: CM, cardiomyocytes; FS, fractional shortening; Shake Sol, shake flask solubility; PB, plasma protein binding.

Early clinical studies have shown that short-term intravenous administration of omecamtiv mecarbil improves cardiac function in patients with chronic heart failure. After 20 weeks of dosing, it have been found the increases in left ventricular systolic ejection time and stroke volume, the decreases in left ventricular systolic and diastolic pressure volume, and the decreases in plasma natriuretic peptide levels and heart rate. Results of a randomized, placebo-controlled trial involving three groups showed that heart failure patients with reduced ejection fraction who received omecamtiv mecarbil had a lower risk of heart failure events and cardiovascular death compared with those who received a placebo.[9] [59] [62]

The Phase III trial of omecamtiv mecarbil (GALACTIC-HF trial) has now been completed and is seeking approval for market release. The results of the trial showed that, after omecamtiv mecarbil treatment, an absolute reduction in heart failure events or cardiovascular death was only 2.1%.[59] [63] [64] Due to its limited efficacy and its impact on cardiac relaxation, the FDA ultimately declined to approve omecamtiv mecarbil. Analysis of data from GALACTIC-HF and Phase II trials showed an association between increased concentrations of the drug and elevated levels of cardiac troponin I and/or NT-proBNP, indicating a correlation with adverse cardiac events such as myocardial ischemia and heart failure.[63] [64] Given the above, omecamtiv mecarbil has greater benefits for patients with LVEF (≤ 28%).[63] [64] Furthermore, the composite endpoint of the first cardiovascular event or cardiovascular death was significantly lower in patients classified as having severe heart failure. Therefore, in the current limited treatment landscape, omecamtiv mecarbil may become a frontline hope for patients with significantly reduced systolic function and severe heart failure.

Recent studies have revealed that both drugs target the same pocket, with no observed differences in the active sites ([Fig. 9]).[30] However, there are differences in the size and conformation of the drug-binding pockets among the structures of omecamtiv mecarbil, mavacamten, and the protein without compound. Compared with the elongated omecamtiv mecarbil, mavacamten is shorter and wider and exhibits a different spatial structure. Consequently, the binding sites also differ, with the isobutyl group of mavacamten uniquely interacting with the N-terminal Leu120. In contrast, the methyl-piperidine of omecamtiv mecarbil reaches the junction residues before the HE helix and the last helix of the converter (K146, R147, HE N160, Conv-H3 A767), while the methyl-pyridine reaches the other end of the omecamtiv mecarbil molecule at the relay (H492, E497). These differences lead to distinct actions of the two drugs in modulating cardiac myosin.[30]

Fig. 9 Mavacamten and omecamtiv mecarbil target the same pocket (PDB code: 8QYP). (A) Cartoon and schematic representation of Mavacamten binding site. (B) Cartoon and schematic LigPlot based34 representation of omecamtiv mecarbil binding site. (C) and (D) Distinct shapes of the pocket where mavacamten and omecamtiv mecarbil bind lead to different distances between the Converter and the motor domain, as shown by the distance between Y164 and N711 in the drug-bound structures. Reproduced with permission from Auguin et al.[30])

 

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Danicamtiv

Danicamtiv (MYK-491) is a promising novel cardiac myosin activator in addition to omecamtiv mecarbil, sharing a similar mechanism of action with omecamtiv mecarbil, both targeting cardiac myosin.[63] [65] They selectively boost the activity of cardiac muscle by increasing the rate of phosphate release and enhancing the availability of active cardiac myosin. It was shown that danicamtiv has a modest impact on left ventricular diastolic stiffness, relaxation, and Ca²⁺ levels in canine heart failure experimental models and HFrEF.[66] [67] Additionally, danicamtiv improves left atrium volume and function, an effect that warrants further investigation, and may be associated with patients suffering from HFrEF and atrial fibrillation.[66] Danicamtiv's synthetic route was illustrated in [Fig. 10].[68]

Fig. 10 Danicamtiv synthesis.

Current research has directly compared the effects of omecamtiv and danicamtiv on myocardial function.[69] [70] The results indicate that although both small molecules exert similar effects on the myocardium, such as dose-dependent positive inotropic effects and improved contractile kinetics, danicamtiv causes less damage to diastolic function while achieving the same increase in stroke volume, effectively improving the main defect of omecamtiv mecarbil. This characteristic may provide a broader therapeutic window in its clinical trials. Currently, in Phase II clinical trials, danicamtiv aims to assess its effectiveness in treating patients with dilated cardiomyopathy caused by MYH7 or TTN gene mutations.[20] [63] [68] However, in addition to omecamtiv mecarbil and danicamtiv, there are several other cardiac myosin activator drugs in development, such as CK-0689705, CK-1122534, CK-1213296, CK-1316719, CK-689705, etc., which are currently in preclinical studies. Currently, only mavacamten and omecamtiv mecarbil have completed Phase III clinical trials.

 

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Conclusion and Prospects

The urgent need for novel therapeutic agents for conditions such as heart failure and HCM cannot be overstated. Mavacamten, the first-in-class drug targeting cardiac myosin, has successfully entered the market, and several other candidates are currently undergoing clinical development. This review has aimed to highlight the research progress surrounding these innovative drug candidates.

This study summarizes the cardiac myosin modulators, from a structural standpoint, that are presently in clinical stages, and comparative analysis reveals that these compounds share notable structural similarities. Aficamten, omecamtiv mecarbil, and danicamtiv all exhibit an elongated conformation in three-dimensional space, with linkers between their rings consisting primarily of hydrophilic or hydrogen bond donor motifs, such as urea, amide, or amine. Importantly, both aficamten and danicamtiv contain an imidazole ring. These structural similarities raise important questions regarding their mechanisms of action, in particular, whether they modulate cardiac myosin through analogous binding interactions and whether they target the same binding sites. However, without corresponding protein binding diagrams, definitive conclusions remain elusive at this stage. Future medicinal chemistry research will benefit from the application of artificial intelligence technologies in protein structure prediction, alongside virtual screening methods to identify novel scaffold molecules.

Clinically, these drugs have demonstrated significant improvements in symptoms and cardiac function for patients with heart failure or HCM. Despite these clinical benefits, they are associated with specific side effects and safety concerns, such as the potential for arrhythmias and hypotension. This risk-benefit dichotomy, therefore, leaves open the question of whether these agents can replace existing treatments. With this uncertainty, the current therapeutic landscape remains constrained by both the limited availability of approved agents and the lack of candidates in clinical development. In addition, a substantial gap in longitudinal efficacy and safety data remains, impeding progress toward comprehensive evaluation and translational research in this field.

Against this backdrop, the elucidation of mavacamten and omecamtiv mecarbil protein-binding sites provides critical structural insights. These discoveries establish a foundational framework that may facilitate the discovery of novel small-molecule myosin modulators through scaffold diversification. Future research directions include, but are not limited to: the systematic use of computer-aided drug design to explore heterocyclic core structures targeting the identified allosteric sites and nucleotide-binding regions, aiming to develop compounds with enhanced potency and reduced toxicity. Importantly, given the unique mechanism by which myosin modulators differ from existing therapies for HCM and heart failure (e.g., sodium-glucose cotransporter 2 inhibitors, β-blockers), rational combination regimens could be explored to achieve synergistic therapeutic benefits while mitigating cumulative adverse effects.

In conclusion, cardiac myosin continues to emerge as a promising and effective therapeutic target and opens new avenues for the treatment of related diseases, and instills hope for the potential to overcome and even cure these challenging conditions.

 

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Conflict of Interest

None declared.

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Publication History

Received: 05 November 2024

Accepted: 30 June 2025

Article published online:
18 August 2025