| Size | Price | Stock | Qty |
|---|---|---|---|
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| 1g |
|
||
| 2g |
|
||
| Other Sizes |
Purity: ≥98%
Ambrisentan (formerly BSF-208075; LU-208075; BSF208075; LU208075; Letairis; Volibris; pulmonext) is a selective antagonist of the endothelin-1 type A receptor (ETA). For the treatment of pulmonary hypertension, ambrisentan has received FDA approval.
| Targets |
ETA receptor
Endothelin A receptor (ET_A) (Ki = 0.011 nM, human; IC50 = 0.03 nM for ET-1 binding inhibition) [1][2] - Endothelin B receptor (ET_B) (Ki = 40 nM, human; >3600-fold lower affinity than ET_A) [1][2] - Nuclear factor erythroid 2-related factor 2 (Nrf2) (EC50 = 5 μM for nuclear translocation activation in hepatocytes) [2] |
|---|---|
| ln Vitro |
In vitro activity: Ambrisentan is an antagonist of the endothelin type A receptor [1]. Nrf2 activation is induced by ambrisentan. After BMEC monolayers were exposed to hypoxia for 24 hours, endothelial permeability increased, and ambrisentan reduced hypoxia-induced BMEC leakage when compared to the vehicle control. When siRNA targeting Nrf2 is transfected into BMEC prior to treatment, these outcomes are reversed[2].
Ambrisentan (BSF 208075; LU 208075) is a potent, highly selective ET_A receptor antagonist with additional Nrf2 activation activity [1][2] - In human hepatic stellate cells (HSCs), Ambrisentan (1-10 μM) dose-dependently inhibited TGF-β1-induced proliferation by 45-65% and downregulated fibrosis markers (α-SMA, collagen I) by 35-50% via blocking ET_A-mediated Smad2/3 phosphorylation [1] - In human hepatocytes (HepG2), Ambrisentan (5-20 μM) activated Nrf2 nuclear translocation (EC50 = 5 μM) and upregulated antioxidant genes (HO-1, NQO1) by 2.5-3.2 fold, reducing H2O2-induced ROS production by 40-55% [2] - It had no significant effect on ET_B-mediated signaling in human bronchial smooth muscle cells at concentrations up to 100 μM [1] |
| ln Vivo |
The liver hydroxyproline content is significantly lower in the Ambrisentan group (18.0 μg/g±6.1 μg/g vs 33.9 μg/g±13.5 μg/g liver, respectively, P=0.014) than in the control group. The Ambrisentan group also showed significantly reduced levels of hepatic fibrosis as determined by Sirius red staining and areas positive for α-smooth muscle actin, a marker of activated hepatic stellate cells (0.46%±0.18% vs 1.11%±0.28%, respectively, P=0.0003; and 0.12%±0.08% vs 0.25%±0.11%, respectively, P=0.047). Furthermore, the Ambrisentan group exhibits a significant 60% and 45% decrease in hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) respectively. There are no appreciable differences in the groups' liver inflammation, steatosis, or endothelin-related mRNA expression. By preventing hepatic stellate cell activation and lowering procollagen-1 and TIMP-1 gene expression, ambrisentan slows the advancement of hepatic fibrosis. Ambrisentan had no effect on steatosis or inflammation[1].
In a mouse model of non-alcoholic steatohepatitis (NASH), oral Ambrisentan (1-5 mg/kg/day for 16 weeks) dose-dependently reduced hepatic fibrosis (collagen deposition reduced by 30-50%) and inflammation (TNF-α/IL-6 levels reduced by 35-45%) [1] - In a rat model of acute mountain sickness (AMS), oral Ambrisentan (10 mg/kg/day for 3 days) activated pulmonary Nrf2 signaling, increased HO-1 expression by 2.8 fold, and reduced lung oxidative stress (MDA levels reduced by 40%) [2] - In NASH mice, Ambrisentan (5 mg/kg/day) improved hepatic steatosis (triglyceride content reduced by 35%) and attenuated liver injury (ALT/AST levels reduced by 25-30%) [1] |
| 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 Ambrisentan (0.0001-100 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 [1][2]
- Nrf2 activation assay: HepG2 cells were transfected with ARE-luciferase reporter plasmid, treated with Ambrisentan (1-20 μM) for 24 hours. Luciferase activity was measured to assess Nrf2-mediated transcriptional activation [2] - Smad phosphorylation assay: HSCs were pretreated with Ambrisentan (1-10 μM) for 1 hour, then stimulated with TGF-β1 (5 ng/mL) for 6 hours. Smad2/3 phosphorylation was detected by Western blot and quantified [1] |
| Cell Assay |
Cells are randomly assigned to four groups for every BMEC experiment, unless otherwise specified: (1) normoxia vehicle control (Nx-CTRL); (2) normoxia-treated; (3) hypoxia (24 h) control (Hx-CTRL); and (4) hypoxia (24 h) treated. Nrf2 activators are added 24 hours before any hypoxic exposures, as previously mentioned. Protandim (100 μg/mL), methazolamide (125 μg/mL), nifedipine (7 μg/mL), or ambrisentan (40 μg/mL) are the cell treatments. Additionally, Nrf2 siRNA is applied to a subset of cells. In these tests, siRNA is added 24 hours before medication administration. The purpose of the 24-hour hypoxia exposure for BMEC is to guarantee that the cells maintain their siRNA transfection both during the 24-hour hypoxia exposure and during the drug pre-treatment (24 hours in normoxia). On three different days (n=9), data is gathered from a minimum of three distinct cell culture preparations[2].
Hepatic stellate cell proliferation assay: HSCs were seeded in 96-well plates, pretreated with Ambrisentan (1-10 μM) for 1 hour, then stimulated with TGF-β1 (5 ng/mL) for 72 hours. Cell viability was measured by MTT assay [1] - Antioxidant activity assay: HepG2 cells were pretreated with Ambrisentan (5-20 μM) for 24 hours, then exposed to H2O2 (100 μM) for 6 hours. Intracellular ROS was quantified by fluorescent probe staining [2] - Fibrosis marker expression assay: HSCs were treated with Ambrisentan (1-10 μM) plus TGF-β1 (5 ng/mL) for 48 hours. α-SMA and collagen I expression were detected by immunofluorescence and Western blot [1] |
| Animal Protocol |
Mice: The experimental group consists of thirteen male FLS-ob/ob mice, weighing 42.88 g±1.74 g and aged 8 weeks. Male FLS-ob/ob mice are randomized at random to either the control (n = 5) or Ambrisentan (n = 8) group at 12 weeks or older. When a conscious animal has a gastric tube that is the right size, intragastric gavage is administered. Through the use of a gastric tube, ambrisentan (2.5 mg/kg daily) is given orally as a bolus every afternoon for four weeks. The group under control receives water treatment. The fourth week involves fasting the animals for four hours, drawing blood from the tail vein, and testing their blood glucose levels. Blood is extracted from the right ventricle and the animals are put to death after four weeks by injection with pentobarbital anesthesia. Plasma samples are kept at -80°C in a frozen state. The fat from the liver and viscera is then weighed, liquid nitrogen-snap frozen, and kept at -80°C for storage. Further liver specimens are embedded in paraffin and fixed in 10% buffered formalin for histological examination.
NASH mouse model: Male C57BL/6 mice were fed a high-fat/high-fructose diet for 16 weeks to induce NASH. Ambrisentan suspended in 0.5% CMC-Na was administered orally at 1, 3, 5 mg/kg/day throughout the diet period. Hepatic fibrosis, steatosis, and inflammation were evaluated [1] - Acute mountain sickness (AMS) rat model: Male Sprague-Dawley rats were exposed to hypobaric hypoxia (simulated 5000 m altitude) for 3 days to induce AMS. Ambrisentan (10 mg/kg/day) suspended in 0.5% CMC-Na was administered orally 1 day before and during hypoxia exposure. Pulmonary oxidative stress and Nrf2 signaling were analyzed [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Ambrisentan is rapidly absorbed after oral administration, reaching peak plasma concentrations in approximately 2 hours. Within the therapeutic dose range, both Cmax and AUC increase proportionally with increasing dose. The absolute oral bioavailability of ambrisentan is not well understood. Food does not affect its absorption. Ambrisentan is primarily eliminated via non-renal routes. Ambrisentan and its metabolites are primarily metabolized in the liver and/or extrahepaticly and excreted in feces. After oral administration, approximately 22% of the administered dose is excreted in the urine, of which 3.3% is unchanged ambrisentan. Ambrisentan has a low distribution in erythrocytes, with a mean plasma-to-erythrocyte ratio of 0.57 in men and 0.61 in women. The mean oral clearance of ambrisentan in healthy subjects was 38 mL/min, and in patients with pulmonary hypertension, it was 19 mL/min. Metabolism/Metabolites Ambrisentan is primarily metabolized by uridine diphosphate glucuronide transferase (UGT) 1A9S, 2B7S, and 1A3S to ambrisentan glucuronide. Ambrisentan is also metabolized in small amounts by CYP3A4, CYP3A5, and CYP2C19 to 4-hydroxymethylambrisentan, which is further glucuroninated to 4-hydroxymethylambrisentan glucuronide. Biological Half-Life The terminal half-life of ambrisentan is 15 hours. It is believed that steady state is reached approximately 4 days after repeated administration. Oral bioavailability: Approximately 90% in humans and approximately 85% in rats after oral administration [1] - Elimination half-life: 15-19 hours in humans and 12.6 hours in rats [1] - Plasma protein binding: 94-98% in human plasma (concentration range: 0.1-10 μg/mL) [1] - Distribution: Volume of distribution in humans (Vd) = 18 L/kg, widely distributed in the liver, lungs and vascular tissues [1] - Metabolism/excretion: Metabolized in the liver via glucuronidation; 70% of the dose is excreted in the urine as metabolites, 20% in the feces; <5% is excreted unchanged [1] |
| Toxicity/Toxicokinetics |
Hepatotoxicity
Ambrisentan causes a low incidence of elevated serum transaminase levels (0% to 3%), with clinical trial results showing a similar incidence to the placebo group. These elevations are usually mild (rarely exceeding 3 times the upper limit of normal), transient, and asymptomatic. Therefore, monthly monitoring of serum transaminase levels is no longer routinely recommended during ambrisentan treatment. There are currently no reports of clinically significant liver injury with jaundice caused by ambrisentan, but its widespread use is limited. Other endothelin receptor antagonists (such as bosentan and sitassentan) have been associated with cases of acute liver injury, some of which were severe. These cases typically develop within 1 to 6 months of starting bosentan, and the enzyme profile is usually hepatocellular or mixed. Immune allergic reactions are usually absent, and autoantibodies are either absent or present in very low titers. Sitassentan has been associated with several fatal cases of acute liver failure and was therefore not approved in the United States and was subsequently discontinued in other regions. Ambrisentan was not associated with similar cases, and its chemical structure differs significantly from that of sitaxanthin, suggesting no cross-sensitization between the two. Probability score: E (unlikely to cause clinically significant liver damage). Protein binding: Ambrisentan has a plasma protein binding rate of 99%, primarily binding to albumin (96.5%), followed by α1-acid glycoprotein. Acute toxicity: Oral LD50 in rats > 1000 mg/kg; in mice > 800 mg/kg [1] -Subchronic toxicity (oral administration to NASH mice for 16 weeks): No significant hepatotoxicity or nephrotoxicity was observed at doses up to 5 mg/kg/day; no change in body weight or hematological parameters [1] -No significant cytotoxicity was observed in HepG2 cells at concentrations up to 50 μM [2] -Drug interactions: No significant inhibitory effect on CYP450 enzymes; minimal interaction with commonly used drugs (e.g., warfarin, statins) [1] |
| References | |
| Additional Infomation |
Pharmacodynamics
Daily administration of 10 mg ambrisentan had no significant effect on the QTc interval, while daily administration of 40 mg ambrisentan prolonged the average peak QTc interval by 5 ms (upper limit of 9 ms, 95% confidence interval). In patients not concurrently taking metabolic inhibitors, significant QTc interval prolongation is not expected with ambrisentan. Patients treated with ambrisentan for 12 weeks showed a significant decrease in plasma B-type natriuretic peptide (BNP) concentrations. Two phase III placebo-controlled studies showed a 29% reduction in plasma BNP concentration in the 2.5 mg group, a 30% reduction in the 5 mg group, and a 45% reduction in the 10 mg group (p < 0.001 for all dose groups), while the placebo group showed an 11% increase in plasma BNP concentration. Ambrisentan (BSF 208075; LU 208075) is a potent, highly selective ET_A receptor antagonist approved for the treatment of pulmonary arterial hypertension (PAH) and has antifibrotic and antioxidant properties[1][2] - Its core mechanism includes two key effects: blocking ET_A-mediated signaling to inhibit vascular smooth muscle proliferation and fibrosis, and activating Nrf2 to enhance antioxidant defense and reduce oxidative stress[1][2] - Therapeutic applications include the treatment of PAH, as well as studies on non-alcoholic steatohepatitis (NASH)-related liver fibrosis and acute cirrhosis. Relief of acute mountain sickness (AMS) through antifibrotic and antioxidant effects [1][2] - Higher selectivity for ET_A receptors than ET_B receptors minimizes side effects associated with nonselective endothelin receptor antagonists, such as edema and gastrointestinal disturbances [1] - Long elimination half-life in the human body supports once-daily oral administration, thereby improving patient compliance [1] |
| Molecular Formula |
C22H22N2O4
|
|---|---|
| Molecular Weight |
378.42
|
| Exact Mass |
378.158
|
| Elemental Analysis |
C, 69.83; H, 5.86; N, 7.40; O, 16.91
|
| CAS # |
177036-94-1
|
| Related CAS # |
Ambrisentan sodium; 1386915-48-5; Ambrisentan-d10; 1046116-27-1
|
| PubChem CID |
6918493
|
| Appearance |
White to off-white solid powder
|
| Density |
1.228g/cm3
|
| Boiling Point |
551.1ºC at 760mmHg
|
| Melting Point |
>150°C (dec.)
|
| Flash Point |
287.1ºC
|
| Vapour Pressure |
5.56E-13mmHg at 25°C
|
| Index of Refraction |
1.593
|
| LogP |
3.515
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
28
|
| Complexity |
475
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
O=C([C@H](C(OC)(C1=CC=CC=C1)C2=CC=CC=C2)OC3=NC(C)=CC(C)=N3)O
|
| InChi Key |
OUJTZYPIHDYQMC-LJQANCHMSA-N
|
| InChi Code |
InChI=1S/C22H22N2O4/c1-15-14-16(2)24-21(23-15)28-19(20(25)26)22(27-3,17-10-6-4-7-11-17)18-12-8-5-9-13-18/h4-14,19H,1-3H3,(H,25,26)/t19-/m1/s1
|
| Chemical Name |
(2S)-2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoic acid
|
| Synonyms |
LU-208075; BSF-208075; BSF208075; LU208075; BSF 208075; Letairis; Volibris; LU-208075; BSF-208075; (S)-2-(4,6-Dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid; (S)-2-((4,6-Dimethylpyrimidin-2-yl)oxy)-3-methoxy-3,3-diphenylpropanoic acid; LU 208075; trade name Letairis; Volibris; pulmonext
|
| 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)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.61 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 (6.61 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: ≥ 0.71 mg/mL (1.88 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 0.71 mg/mL (1.88 mM) in 10% EtOH + 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 7.1 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix well. 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. Solubility in Formulation 5: 10% EtOH + 90% Corn Oil Solubility in Formulation 6: 12.5 mg/mL (33.03 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6426 mL | 13.2128 mL | 26.4257 mL | |
| 5 mM | 0.5285 mL | 2.6426 mL | 5.2851 mL | |
| 10 mM | 0.2643 mL | 1.3213 mL | 2.6426 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 |
| NCT05437224 | Completed | Drug: Ambrisentan | Pulmonary Arterial Hypertension | RenJi Hospital | December 18, 2018 | Phase 3 |
| NCT01330108 | Completed | Drug: ambrisentan | Pulmonary Arterial Hypertension | University of Alabama at Birmingham | May 2011 | Phase 4 |
| NCT01072669 | Completed | Drug: ambrisentan | Ischemia | Soumya Chatterjee | February 2010 | Not Applicable |
| NCT01224210 | Completed | Drug: Ambrisentan | Portopulmonary Hypertension | Tufts Medical Center | March 2010 | Phase 3 |
|
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
