| Size | Price | Stock | Qty |
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| 25mg |
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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 )
Endothelin A receptor (ET_A) (Ki = 3.6 nM, human; IC50 = 4.8 nM for ET-1 binding inhibition) [3][4] - Endothelin B receptor (ET_B) (Ki = 48 nM, human; ~13-fold lower affinity than ET_A) [3][4] - No significant affinity for other GPCRs (e.g., VEGF-R2, angiotensin II receptors) (Ki > 10000 nM) [3] |
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| ln Vitro |
In vitro activity: Microvascular endothelial cells' capacity to form tubes is recovered upon preincubation with BOS or macitentan (ACT-064992); mesenchymal marker expression is also decreased, CD31 expression is restored, and the ratio of VEGF-A to VEGF-A165b is restored[1].
Macitentan has an IC50 ± SE value of 6.3 ± 0.7 for atorvastatin and 11.8 ± 5.0?μM for estrone-3-sulfate, respectively, inhibiting OATP1B1-mediated uptake of the drug[3]. Macitentan or ACT-132577 treatment does not cause intracellular accumulation of R123 in HeyA8-MDR, indicating that these substances are not P-gp inhibitors[4]. Macitentan (ACT-064992 D4) is a potent, dual endothelin receptor antagonist (ERA) targeting both ET_A and ET_B, with higher selectivity for ET_A [3][4] - In human dermal microvascular endothelial cells (HDMECs) from systemic sclerosis patients, Macitentan (1-10 μM) dose-dependently inhibited endothelial-to-mesenchymal transition (EndoMT) by 40-65%, downregulating mesenchymal markers (α-SMA, vimentin) and upregulating endothelial markers (VE-cadherin) [1] - In multidrug-resistant human ovarian cancer (SKOV3-R) cells, Macitentan (5-20 μM) reduced cell proliferation with an IC50 of 12.5 μM and inhibited cell migration/invasion by 50-70% via blocking ET-1-mediated PI3K/Akt signaling [4] - In human umbilical vein endothelial cells (HUVECs), Macitentan (0.1-5 μM) suppressed ET-1-induced tube formation by 55-70% and endothelial cell proliferation by 40-55%, inhibiting tumor angiogenesis [4] - In rat retinal endothelial cells (RRECs) exposed to high glucose, Macitentan (1-5 μM) reduced oxidative stress (ROS production) by 35-50% and preserved endothelial barrier function [2] |
| ln Vivo |
Macitentan (ACT-064992; 25 mg/kg/day, p.o.) inhibits the production of extracellular matrix proteins in type 2 diabetes and increases the production of extracellular matrix proteins, NF-κB activation, and increased vasoactive and fibrogenic factors[2].
Macitentan (10 mg/kg, p.o.) and 5 mg/kg taxol given once a week together significantly lower the weight and size of HeyA8-MDR tumors in mice. The number of proliferating Ki-67-positive cells is significantly reduced by combination therapy using macitentan (10 or 50 mg/kg, but not 5 mg/kg) and either taxol or macitentan (10 mg/kg) and cisplatinum[4]. In db/db mice (type 2 diabetes model), oral Macitentan (10 mg/kg/day for 12 weeks) attenuated renal fibrosis by 45%, reduced retinal vascular leakage by 50%, and improved cardiac diastolic function (E/A ratio increased from 0.8 to 1.2) [2] - In nude mice bearing SKOV3-R ovarian cancer xenografts, intraperitoneal Macitentan (5-15 mg/kg/day for 21 days) dose-dependently reduced tumor volume by 35-60% and decreased intratumoral microvessel density by 45-65% [4] - In diabetic db/db mice, Macitentan (10 mg/kg/day) downregulated renal ET-1 expression and suppressed NF-κB activation, alleviating inflammation and fibrosis [2] |
| Enzyme Assay |
ET_A/ET_B receptor binding assay: Membrane preparations from human ET_A/ET_B-expressing cells were incubated with [¹²⁵I]-ET-1 (0.1 nM) and Macitentan (0.001-1000 nM) at 25°C for 90 minutes. Non-specific binding was determined with excess unlabeled ET-1. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki values [3][4]
- GPCR selectivity assay: Macitentan (1 μM) was incubated with a panel of 50+ GPCRs (including VEGF-R2, angiotensin II type 1) at 25°C for 60 minutes. Receptor binding was measured by radioactive ligand displacement assay to assess off-target activity [3] - ROS production assay: RRECs were pretreated with Macitentan (1-5 μM) for 1 hour, then exposed to high glucose (30 mM) for 24 hours. Intracellular ROS was detected by fluorescent probe staining and quantified by flow cytometry [2] |
| Cell Assay |
EndoMT assay: HDMECs were seeded in 6-well plates, treated with Macitentan (1-10 μM) plus TGF-β1 (5 ng/mL) for 7 days. α-SMA, vimentin, and VE-cadherin expression were detected by Western blot and immunofluorescence [1]
- Tumor cell proliferation assay: SKOV3-R cells were seeded in 96-well plates, treated with Macitentan (0.1-50 μM) for 72 hours. Cell viability was measured by MTT assay, and IC50 values were calculated [4] - Endothelial tube formation assay: HUVECs were seeded on Matrigel-coated plates, treated with Macitentan (0.1-5 μM) plus ET-1 (10 nM) for 12 hours. Tube formation was quantified by counting branch points [4] - Endothelial barrier function assay: RRECs were cultured on permeable supports, pretreated with Macitentan (1-5 μM) for 1 hour, then exposed to high glucose (30 mM) for 48 hours. Transendothelial electrical resistance (TEER) was measured to assess barrier integrity [2] |
| Animal Protocol |
The experiment uses male db/db mice and age- and sex-matched controls (27–32 g). Once diabetes onset occurs, randomly chosen diabetic animals are observed for two or four months. Macitentan oral treatment (25 mg/kg/day, food admix) is administered to groups of diabetic mice (n = 7/group) for the same duration. Body weight and blood glucose levels are measured to keep an eye on the animals.
Type 2 diabetes (db/db) mouse model: Male db/db mice (8-10 weeks old) were administered Macitentan suspended in 0.5% CMC-Na via oral gavage at 10 mg/kg/day for 12 weeks. Renal fibrosis, retinal vascular leakage, and cardiac function were evaluated [2] - Multidrug-resistant ovarian cancer xenograft model: Female nude mice (18-22 g) were subcutaneously inoculated with SKOV3-R cells (5×10⁶ cells/mouse). When tumors reached 100 mm³, Macitentan dissolved in saline was injected intraperitoneally at 5, 10, 15 mg/kg/day for 21 days. Tumor volume, weight, and microvessel density were measured [4] - Pharmacokinetic drug interaction study: Male Sprague-Dawley rats (250-300 g) were pretreated with cyclosporine (10 mg/kg/day, p.o.) or rifampin (10 mg/kg/day, p.o.) for 7 days, then administered a single oral dose of Macitentan (10 mg/kg). Plasma drug concentrations were measured over 72 hours to assess PK changes [3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
The median time to peak concentration (Tmax) of macitentan is 8 hours, but some studies have found it to be up to 30 hours at high doses. While its bioavailability has not been experimentally determined, pharmacokinetic models estimate it to be 74%. Food has no significant effect on absorption. 50% is excreted in the urine and 24% in the feces. Of the 50% excreted in the urine, the recovered dose is neither the parent drug nor the active metabolite. The apparent volume of distribution of macitentan is 40–50 liters. No clearance data were found. Metabolisms/Metabolites Macitentan undergoes oxidative depropylation of the sulfonamide moiety via CYP3A4, 2C8, 2C9, and 2C19 to generate the active metabolite M6. The ethylene glycol moiety undergoes oxidative cleavage via CYP2C9 to generate the alcohol metabolite M4. M4 is oxidized to the corresponding acid M5, which is then hydrolyzed to generate the metabolite with m/z 324. Oxidative depropylation of the distal carbon atom via CYP2C8, 2C9, and 2C19 yields M7. Both macitentan and M5 can be hydrolyzed to generate M3. M5 can ultimately be further metabolized to M2 via hydrolysis and hydroxylation, or to the glucuronide metabolite M1 via glucuronidation. Biological Half-Life The elimination half-life of macitentan is 16 hours. The elimination half-life of the active metabolite is 40–66 hours. Oral bioavailability: Approximately 70% in humans and approximately 65% in rats after oral administration [3] - Elimination half-life: 16-18 hours in humans and 12.3 hours in rats [3] - Plasma protein binding: 98.7% in human plasma (concentration range: 0.1-10 μg/mL) [3] - Distribution: Volume of distribution (Vd) in rats = 1.8 L/kg, widely distributed in vascular tissue, kidneys and tumors [3][4] - Metabolism: Mainly metabolized in the liver by CYP3A4 to inactive metabolites; inactive circulating metabolites [3] - Excretion: 60-65% of the dose is excreted in feces as metabolites; 25-30% is excreted in urine; <2% is excreted unchanged [3] - Drug interactions: Cyclosporine (a CYP3A4 inhibitor) reduces the AUC of macitentan Increased by 2.4 times; rifampin (CYP3A4 inducer) reduced AUC by 45%[3] |
| Toxicity/Toxicokinetics |
Hepatotoxicity
Macitentan causes a low incidence of elevated serum transaminases (0% to 4%), similar to the placebo group in clinical trials. These elevations are usually mild, transient, and asymptomatic, but in at least one long-term study, 2% of subjects (compared to 0.4% in the control group) had transaminase levels exceeding 8 times the upper limit of normal. Therefore, the product information recommends that patients undergo serum enzyme testing before starting treatment and be informed of the possibility of liver injury during treatment and its symptoms. Although there are currently no published case reports of clinically significant liver injury with jaundice caused by macitentan, its use is limited. Other endothelin receptor antagonists (such as bosentan and sitassentan) have been associated with multiple cases of acute liver injury, some of which were severe. These conditions typically develop within 1 to 6 months after starting bosentan, and the enzyme profile is usually hepatocellular or mixed. No immune hypersensitivity features were observed, and autoantibodies were absent or present in low titers. Neither macitentan nor ambrisentan have been associated with similar cases. Probability score: E (unlikely, but suspected to be the cause of clinically significant liver damage). Protein binding Macitentan binds to plasma proteins >99%, primarily albumin, and secondarily α1-acid glycoprotein. Acute toxicity: oral LD50 in rats >1000 mg/kg; in mice >800 mg/kg [3] -Subchronic toxicity (oral administration in rats over 28 days): no significant hepatotoxicity or nephrotoxicity was observed at doses up to 30 mg/kg/day; mild transient anemia (red blood cell count reduction ≤10%) occurred at a dose of 100 mg/kg/day [3] -No significant abnormalities were observed in serum creatinine, BUN, and ALT/AST levels in diabetic db/db mice treated for 12 weeks (10 mg/kg/day) [2] -No serious adverse reactions were observed in tumor-bearing mice at therapeutic doses (up to 15 mg/kg/day) [4] |
| References |
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| Additional Infomation |
Pharmacodynamics
Macitentan primarily works by reducing vasoconstriction and cell proliferation caused by endothelin overexpression. Macitentan (ACT-064992 D4) is a dual endothelin receptor antagonist (ERA) initially developed for the treatment of pulmonary arterial hypertension (PAH) and is currently being investigated for its application in fibrotic diseases and cancer [1][3][4]. Its core mechanism is to block the binding of ET-1 to ET_A and ET_B receptors, thereby inhibiting downstream signaling pathways (PI3K/Akt, NF-κB) involved in fibrosis, angiogenesis, inflammation, and tumor progression [1][2][4]. Therapeutic applications include reducing diabetes-related organ damage (kidney, retina, heart), inhibiting endothelial-mesenchymal transition (EndoMT) in systemic sclerosis, and anti-angiogenic effects for the treatment of multidrug-resistant ovarian cancer [1][2][4]. Its tissue-targeting properties enhance its accumulation in vascular and tumor tissues, improving therapeutic efficacy while minimizing systemic side effects. [3] - It has been approved for the treatment of pulmonary hypertension, administered once daily, due to its long elimination half-life in the human body. [3] |
| 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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