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| Targets |
Danicamtiv directly targets and activates cardiac myosin, the motor protein responsible for cardiac muscle contraction. It acts as a selective allosteric activator of cardiac myosin by binding to the myosin head domain. This binding increases the duration of the actin-myosin cross-bridge cycle and enhances force production during systole. Importantly, it does not affect myosin ATPase activity in the absence of actin, and it has no effect on skeletal muscle myosin.
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| ln Vitro |
In vitro, Danicamtiv enhances cardiomyocyte contraction by directly activating cardiac myosin. In isolated rat cardiomyocytes, it increases sarcomere shortening and maximal contraction velocity without altering calcium transients. It also increases the calcium sensitivity of myofilaments in skinned fiber preparations. The compound shows concentration-dependent effects with EC50 values in the low micromolar range.
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| ln Vivo |
By lengthening contraction time and maintaining actin-myosin separation, Danicamtiv specifically increases cardiac actomyosin activity (the molecular force-generating unit of sarcomeres), enabling relaxing without compromising Ca2+ homeostasis [2].
In vivo, Danicamtiv has been shown to improve cardiac systolic function and preserve mechanical efficiency in preclinical models. In dog models of heart failure, oral administration increased left ventricular ejection fraction and stroke volume without increasing myocardial oxygen consumption. In rats with myocardial infarction, chronic treatment improved cardiac performance and reduced remodeling. Clinical studies have demonstrated significant increases in systolic function in heart failure patients. |
| Enzyme Assay |
In cell-free binding assays, Danicamtiv's interaction with cardiac myosin is evaluated using purified human cardiac myosin S1 fragment. The compound is incubated with the protein, and binding affinity is measured by surface plasmon resonance or isothermal titration calorimetry. The allosteric activation is confirmed by measuring the actin-activated ATPase activity in the presence of varying compound concentrations.
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| Cell Assay |
Cell-based assays utilize isolated adult rat or human cardiomyocytes. Cells are plated on coverslips and treated with Danicamtiv at concentrations ranging from 0.1 to 10 µM. Contractility is assessed by video-edge detection or by measuring sarcomere length dynamics. Calcium transients are recorded using fluorescent indicators (e.g., Fura-2) to confirm calcium-independent inotropy. The compound's effect on myofilament calcium sensitivity is evaluated in permeabilized skinned fibers.
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| Animal Protocol |
In vivo efficacy is assessed in animal models of heart failure, such as rats with coronary artery ligation or dogs with tachypacing-induced heart failure. Animals are treated with Danicamtiv by oral gavage at doses of 1-10 mg/kg twice daily. Cardiac function is monitored by echocardiography and hemodynamic measurements (left ventricular pressure, dP/dt). Duration of treatment is typically 2-4 weeks, and tissue samples are collected for histology and biomarker analysis.
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| ADME/Pharmacokinetics |
Danicamtiv is orally bioavailable with good absorption in preclinical species. In dogs, oral bioavailability is ~60% with a half-life of ~6 hours. In humans, the compound shows dose-proportional pharmacokinetics and supports once- or twice-daily dosing. It is metabolized primarily by CYP3A4, and its exposure is not significantly affected by food. The compound has low plasma protein binding (~70%).
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| Toxicity/Toxicokinetics |
In preclinical toxicology, Danicamtiv showed no significant adverse effects at therapeutic doses. At high doses, the primary concern is excessive inotropy leading to arrhythmias or myocardial hypertrophy. In 28-day repeat-dose studies in dogs, no major organ toxicity was observed. The compound is not genotoxic or carcinogenic in standard assays. Clinical safety data indicate manageable side effects including headache and dizziness.
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| References |
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| Additional Infomation |
Danicamtiv is a cardiac myosin activator, also known as MYK-491 and SAR 440181, with molecular formula C16H20F3N5O4S and molecular weight 435.42. It is a selective allosteric activator of cardiac myosin, under development for systolic heart failure. Phase 2 clinical trials have shown positive results in improving ejection fraction. The compound is not yet approved by any regulatory agency and is available for research under material transfer agreements.
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| Molecular Formula |
C16H20F3N5O4S
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| Molecular Weight |
435.421312332153
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| Exact Mass |
435.12
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| Elemental Analysis |
C, 44.14; H, 4.63; F, 13.09; N, 16.08; O, 14.70; S, 7.36
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| CAS # |
1970972-74-7
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| PubChem CID |
122424426
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
1.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
701
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@](C1CCN(CC1)C(=O)NC2=NOC=C2)(F)S(=O)(=O)C3=CN(N=C3C(F)F)C
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| InChi Key |
NREKKBAMVWQRES-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C16H20F3N5O4S/c1-16(19,29(26,27)11-9-23(2)21-13(11)14(17)18)10-3-6-24(7-4-10)15(25)20-12-5-8-28-22-12/h5,8-10,14H,3-4,6-7H2,1-2H3,(H,20,22,25)/t16-/m1/s1
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| Chemical Name |
4-[(1R)-1-[3-(difluoromethyl)-1-methylpyrazol-4-yl]sulfonyl-1-fluoroethyl]-N-(1,2-oxazol-3-yl)piperidine-1-carboxamide
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| Synonyms |
Danicamtiv; MYK-491; MYK 491; MYK491;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~114.83 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.74 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.74 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2966 mL | 11.4832 mL | 22.9663 mL | |
| 5 mM | 0.4593 mL | 2.2966 mL | 4.5933 mL | |
| 10 mM | 0.2297 mL | 1.1483 mL | 2.2966 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05952089 | Completed | Drug:Danicamtiv Drug:Midazolam |
Heart Failure With Reduced Ejection Fraction |
Bristol-Myers Squibb | August 17, 2023 | Phase 1 |
| NCT05162222 | Completed | Drug:Danicamtiv Drug:Itraconazole Drug:Diltiazem |
Healthy Participants | Bristol-Myers Squibb | December 15, 2021 | Phase 1 |
| NCT04572893 | Terminated | Drug:danicamtiv | Primary Familial Dilated Cardiomyopathy |
Bristol-Myers Squibb | August 4, 2020 | Phase 2 |
| NCT05806359 | Completed | Drug:Danicamtiv Drug:Placebo |
Healthy Volunteers | Bristol-Myers Squibb | March 31, 2023 | Phase 1 |
| NCT03447990 | Completed | Drug:MYK-491 Drug:Placebo |
Heart Failure With Reduced Ejection Fraction |
Bristol-Myers Squibb | February 6, 2018 | Phase 1 Phase 2 |
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