Mavacamten
[CAS# 1642288-47-8]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Ketones
• Name: Mavacamten
• Synonyms: (S)-3-Isopropyl-6-[(1-phenylethyl)amino]pyrimidine-2,4(1H,3H)-dione; 6-[[(1S)-1-phenylethyl]amino]-3-propan-2-yl-1H-pyrimidine-2,4-dione
• Molecular Formula: C₁₅H₁₉N₃O₂
• Molecular Weight: 273.33
• CAS Registry Number: 1642288-47-8
• EC Number: 833-453-5
• SMILES: C[C@@H](C1=CC=CC=C1)NC2=CC(=O)N(C(=O)N2)C(C)C

Properties

• Solubility: Practically insoluble (0.052 g/L) (25 ºC), Calc.^*
• Density: 1.19±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*
• Index of Refraction: 1.591, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08;GHS09 Dander
• Hazard Statements: H302-H319-H332-H372-H400
• Precautionary Statements: P260-P264-P270-P273-P280-P301+P312+P330-P304+P312-P305+P351+P338-P314-P337+P313-P391-P501

Discovory and Applicatios

Mavacamten is a novel, selective small molecule inhibitor of cardiac myosin used primarily for the treatment of hypertrophic cardiomyopathy (HCM), a condition characterized by the thickening of the heart muscle that can lead to heart failure, arrhythmias, and other complications. The discovery of mavacamten emerged from the growing need for therapies that could address the underlying mechanisms of HCM, which was previously managed primarily with symptomatic treatments and surgical interventions.

Hypertrophic cardiomyopathy is often caused by mutations in the genes that code for cardiac sarcomere proteins, leading to abnormal interactions between these proteins. This causes excessive contraction and thickening of the heart muscle, impairing its ability to relax and fill with blood properly. Mavacamten was designed to target and modulate the activity of cardiac myosin, a key protein involved in muscle contraction. By selectively inhibiting myosin, mavacamten reduces the force of contraction and helps to normalize the heart’s pumping function.

The compound was developed by MyoKardia, a biotechnology company focused on cardiovascular diseases. Early research on mavacamten demonstrated that it could specifically reduce the hypercontractility of the heart muscle associated with HCM. This mechanism of action makes mavacamten unique compared to other treatments for HCM, which primarily focus on reducing symptoms or managing arrhythmias.

Mavacamten’s clinical development was accelerated by positive results in early-stage trials, which showed significant improvements in patients' symptoms, exercise capacity, and heart function. In 2020, the U.S. Food and Drug Administration (FDA) approved mavacamten under the brand name Camzyos for the treatment of symptomatic obstructive HCM, making it the first drug specifically approved for this condition. The approval was based on the results of the EXPLORER-HCM trial, a large, multicenter clinical study that demonstrated the efficacy of mavacamten in improving heart function and reducing symptoms in patients with obstructive HCM.

The drug works by binding to cardiac myosin, decreasing its activity and allowing the heart muscle to relax more effectively. This not only reduces the excessive contraction seen in HCM but also helps to improve the heart’s ability to fill with blood, ultimately enhancing overall cardiac function. Patients treated with mavacamten have reported reductions in symptoms such as shortness of breath, fatigue, and chest pain. Additionally, the drug has shown a reduction in left ventricular outflow tract obstruction, a hallmark of obstructive HCM.

Mavacamten is typically administered orally and is well-tolerated, with the most common side effects being mild and transient, such as headache and fatigue. However, as with any cardiac medication, monitoring is necessary to avoid potential adverse effects, such as bradycardia or heart block. The potential for long-term benefits of mavacamten in reducing the progression of HCM remains an area of ongoing research.

Beyond its use in HCM, mavacamten is being investigated for potential applications in other forms of heart failure and cardiovascular diseases. The success of mavacamten in treating hypertrophic cardiomyopathy has opened the door for future therapies that target the molecular mechanisms underlying other cardiac disorders.

In summary, mavacamten represents a significant advancement in the treatment of hypertrophic cardiomyopathy, offering a targeted approach that addresses the underlying pathophysiology of the disease. Its approval marks a milestone in cardiovascular medicine, providing patients with a much-needed therapeutic option for managing a condition that was once difficult to treat.

References

2024. Myosin-Inhibitor Mavacamten Acutely Enhances Cardiomyocyte Diastolic Compliance in Heart Failure With Preserved Ejection Fraction. Circulation: Heart Failure, 17(9).
DOI: 10.1161/circheartfailure.124.011833

2024. Real-world experience in initiation of treatment with the selective cardiomyosin inhibitor mavacamten in an outpatient clinic cohort during the 12-week titration period. Clinical Research in Cardiology, 113(10).
DOI: 10.1007/s00392-024-02544-w

2024. Obstructive hypertrophic cardiomyopathy: from genetic insights to a multimodal therapeutic approach with mavacamten, aficamten, and beyond. The Egyptian Heart Journal, 76(1).
DOI: 10.1186/s43044-024-00587-y