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Purity: ≥98%
Macitentan (formerly ACT-064992; ACT064992; ACT 064992; Opsumit) is an orally bioavailable and non-peptide, dual antagonist of ETA/ETB endothelin (ET) receptor. The medication has received approval to treat PAH, or pulmonary arterial hypertension. With IC50 values of 0.5 ± 0.2 nM (n = 17), it prevents 125I-ET-1 from binding to recombinant ETA receptors in Chinese hamster ovary cells.
| Targets |
ET-A ( IC50 = 0.5 nM ); ET-B ( IC50 = 0.5 nM )
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Macitentan has a median Tmax of 8h although some studies have found up to 30h at higher doses. Although the bioavailability has not been experimentally determined, pharmacokinetic modeling has estimated it at 74%. Food has not been found to have a significant effect on absorption. Eliminated 50% through urine and 24% through feces. Of the 50% excreted through the urine, none of the recovered dose was in the form of the parent drug nor the active metabolite. Macitentan has an apparent volume of distribution of 40-50L. Clearance data was not found. Metabolism / Metabolites Macitentan undergoes oxidative depropylation of the sulfonamide moiety via CYP3A4, 2C8, 2C9, and 2C19 to form the active metabolite M6. The ethylene glycol moiety undergoes oxidative cleavage via CYP2C9 to the alcohol metabolite M4. M4 is oxidized to its corresponding acid, M5, then hydrolyzed to the metabolite termed m/z 324. Oxidative depropylation of a distal carbon atom via CYP2C8, 2C9, and 2C19 forms M7. Hydrolysis of both macitentan and M5 produces M3. Finally M5 may be further metabolized via hydrolysis and hydroxylation to M2 or via glucuronidation to a glucuronide metabolite, M1. Biological Half-Life The half-life of elimination of macitentan is 16 hours. The half-life of elimination of the active metabolite is 40-66h |
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| Toxicity/Toxicokinetics |
Hepatotoxicity
Macitentan is associated with a low rate of serum aminotransferase elevations (0% to 4%) that, in clinical trials, was similar to the rate among placebo recipients. These elevations were usually mild, transient and not associated with symptoms, but were above 8 times the ULN in 2% of subjects (vs 0.4% of controls) in at least one long term study. For these reasons, the product label recommends that patients have serum enzymes tested before starting therapy and be alerted to the possibility and symptoms of liver injury during therapy. While there have been no published reports of clinically apparent liver injury with jaundice associated with macitentan, it has had limited general use. Other endothelin receptor antagonists (bosentan, sitaxentan) have been linked to several instances of acute liver injury, some of which have been severe. The onset of illness was usually within 1 to 6 months of starting bosentan and the enzyme pattern was typically hepatocellular or mixed. Immunoallergic features were not present and autoantibodies absent or present in low titer. Macitentan and ambrisentan have not been linked to similar cases. Likelihood score: E* (unlikely but suspected cause of clinically apparent liver injury). Protein Binding Macitentan is >99% bound to plasma proteins, primarily to albumin and to a lesser extent α1-acid glycoprotein. |
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| Additional Infomation |
Pharmacodynamics
Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression. |
| Molecular Formula |
C19H20BR2N6O4S
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| Molecular Weight |
588.27
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| Exact Mass |
585.96
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| Elemental Analysis |
C, 38.79; H, 3.43; Br, 27.17; N, 14.29; O, 10.88; S, 5.45
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| CAS # |
441798-33-0
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| Related CAS # |
Macitentan-d4; 1258428-05-5; Macitentan (n-butyl analogue); 556797-16-1
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| PubChem CID |
16004692
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| Appearance |
White to off-white solid powder
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| Density |
1.7±0.1 g/cm3
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| Boiling Point |
692.4±65.0 °C at 760 mmHg
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| Melting Point |
134-136°C
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| Flash Point |
372.5±34.3 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.634
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| LogP |
5.41
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
32
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| Complexity |
642
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| Defined Atom Stereocenter Count |
0
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| SMILES |
BrC1=CN=C(OCCOC2=C(C3=CC=C(Br)C=C3)C(NS(NCCC)(=O)=O)=NC=N2)N=C1
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| InChi Key |
JGCMEBMXRHSZKX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)
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| Chemical Name |
5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine
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| Synonyms |
ACT 064992; Macitentan; ACT-064992; ACT064992; trade name: Opsumit
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.25 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 (4.25 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.25 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (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 | 1.6999 mL | 8.4995 mL | 16.9990 mL | |
| 5 mM | 0.3400 mL | 1.6999 mL | 3.3998 mL | |
| 10 mM | 0.1700 mL | 0.8499 mL | 1.6999 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.
A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension (PAH)
CTID: NCT02932410
Phase: Phase 3 Status: Active, not recruiting
Date: 2024-10-09
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Products are for research use only; We do not sell to patients
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