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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.
Physicochemical Properties
| Molecular Formula | C19H20BR2N6O4S |
| Molecular Weight | 588.27 |
| Exact Mass | 585.96 |
| Elemental Analysis | C, 38.79; H, 3.43; Br, 27.17; N, 14.29; O, 10.88; S, 5.45 |
| CAS # | 441798-33-0 |
| Related CAS # | Macitentan-d4; 1258428-05-5; Macitentan (n-butyl analogue); 556797-16-1 |
| PubChem CID | 16004692 |
| Appearance | White to off-white solid powder |
| Density | 1.7±0.1 g/cm3 |
| Boiling Point | 692.4±65.0 °C at 760 mmHg |
| Melting Point | 134-136°C |
| Flash Point | 372.5±34.3 °C |
| Vapour Pressure | 0.0±2.2 mmHg at 25°C |
| Index of Refraction | 1.634 |
| LogP | 5.41 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 11 |
| Heavy Atom Count | 32 |
| Complexity | 642 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | BrC1=CN=C(OCCOC2=C(C3=CC=C(Br)C=C3)C(NS(NCCC)(=O)=O)=NC=N2)N=C1 |
| InChi Key | JGCMEBMXRHSZKX-UHFFFAOYSA-N |
| 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) |
| Chemical Name | 5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine |
| Synonyms | ACT 064992; Macitentan; ACT-064992; ACT064992; trade name: Opsumit |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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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| References |
[1]. Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study. Arthritis Res Ther. 2016 Oct 6;18(1):228. [2]. Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist. Life Sci. 2012 Apr 13. [3]. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012 Mar;14(1):68-78. [4]. Antivascular therapy for multidrug-resistant ovarian tumors by macitentan, a dual endothelin receptor antagonist. Transl Oncol. 2012 Feb;5(1):39-47. |
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| Additional Infomation |
Pharmacodynamics Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression. |
Solubility Data
| 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. 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. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |