Mavacamten Chemical Properties

Density 

1.19±0.1 g/cm3(Predicted)

storage temp. 

Storage temp. -20°C

solubility 

insoluble in H2O; ≥11.32 mg/mL in EtOH with ultrasonic; ≥13.65 mg/mL in DMSO

form 

solid

pka

8.83±0.40(Predicted)

color 

White to off-white

InChI

InChI=1S/C15H19N3O2/c1-10(2)18-14(19)9-13(17-15(18)20)16-11(3)12-7-5-4-6-8-12/h4-11,16H,1-3H3,(H,17,20)/t11-/m0/s1

InChIKey

RLCLASQCAPXVLM-NSHDSACASA-N

SMILES

C1(=O)NC(N[C@H](C2=CC=CC=C2)C)=CC(=O)N1C(C)C

Mavacamten Usage And Synthesis

Description

Mavacamten（MYK-461）is a first-in-class allosteric inhibitor of cardiac myosin that promises to provide clinicians with targeted therapy for these patients. It is a mechanistically novel small molecule that acts on the sarcolemma to specifically inhibit contractility and has been proposed as a treatment for HCM.

Uses

MYK-461 is a drug used to treat obstructive hypertrophic cardiomyopathy as a cardiac myosin inhibitor. Mavacamten is used to treat adults with symptomatic obstructive hypertrophic cardiomyopathy. It is used to treat symptomatic obstructive hypertrophic cardiomyopathy (HCM). 

Application

Mavacamten (trade name Camzyos) is a small molecule cardiac myosin modulator indicated for the treatment of adult patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). oHCM is a monogenic cardiovascular disease caused by mutations in sarcomeric proteins, specifically myosin, that may affect up to 1 in 200 people.

Mechanism of action

Mavacamten is thought to work by reducing cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy and reduced compliance. In clinical and preclinical studies, it has consistently reduced biomarkers of cardiac wall stress, lessened excessive cardiac contractility, and increased diastolic compliance.

Side effects

Common side effects of Mavacamten include: Dizziness, fainting, Incidence not known, Chest pain or tightness, decreased urine output, dilated neck veins, irregular breathing, irregular heartbeat, swelling of the face, fingers, feet, or lower legs, trouble breathing, unusual tiredness or weakness and weight gain.

Synthesis

Using isopropylamine (8.1) as the starting material, urea 8.2 can be obtained by treatment with trimethylsilyl isocyanate in a yield of 58% (Figure 2.3). Cyclization with dimethyl malonate can give the barbituric acid derivative 8.3 in a yield of 50%. The introduction of the chiral amine side chain is carried out in two steps. First, chlorination is carried out using pure phosphorus oxychloride (POCl3) and triethylbenzylammonium chloride (TEBAC) to obtain chloride 8.4 in a yield of 40%, and then it is treated with (S)-α-methylbenzylamine (8.5) to obtain white solid Mavacamten (8) in a yield of 69%.

Drug interactions

Mavacamten has a variable terminal t1/2 that depends on CYP2C19 metabolic status. Mavacamten's terminal half-life is 6-9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days.

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