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Purity: ≥98%
Sitaxentan sodium (formerly IPI-1040; TBC-11251; IPI 1040; TBC11251; Thelin), the sodium salt of Sitaxentan, is a selective and orally bioavailable endothelin A receptor (ETA) antagonist with anti-hypertensive activity. It suppresses ETA with IC50 and Ki of 1.4 nM and 0.43 nM, respectively. For the treatment of pulmonary arterial hypertension (PAH), sitaxentani is an authorized drug.
| Targets |
Endothelin A receptor (ET_A) (Ki = 1.4 nM, human; IC50 = 2.1 nM for ET-1 binding inhibition) [2]
- Endothelin B receptor (ET_B) (Ki = 620 nM, human; >440-fold lower affinity than ET_A) [2] - No significant affinity for other GPCRs (e.g., VEGF-R, angiotensin II receptors) (Ki > 10000 nM) [2] |
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| ln Vitro |
In vitro activity: Sitaxsentan and Bosentan inhibit human hepatic transporters and attenuate NTCP transport at higher concentrations, which offers a possible explanation for the increased hepatotoxicity seen with these drugs in clinical settings. Only sitaxsentan decreased OATP transport (52%)[1]. Both sitaxentan alone and in combination with sildenafil totally inhibit the elevated expressions of the ETB receptor and endothelin-1. Only sitaxentan is able to partially restore BMPR-1A and BMPR-2 expression. While BMPR-1A and BMPR-2 expressions are further restored when sildenafil and sitaxentan are taken together, they are still lower than in controls[3].
Sitaxentan sodium (Sitaxentan; IPI 1040) is a potent, highly selective endothelin A receptor (ET_A) antagonist, with minimal activity against ET_B [2] - In human ET_A-expressing CHO cells, Sitaxentan sodium (0.01-100 nM) dose-dependently inhibited [¹²⁵I]-ET-1 binding with an IC50 of 2.1 nM, blocking ET_A-mediated calcium mobilization [2] - In human pulmonary artery smooth muscle cells (PASMCs), Sitaxentan sodium (1-10 μM) suppressed ET-1-induced cell proliferation by 50-70% and reduced collagen synthesis [2] - In sandwich-cultured human hepatocytes, Sitaxentan sodium (1-50 μM) was identified as a substrate of hepatobiliary transporters (OATP1B1/1B3, BSEP), with no significant inhibition of transporter activity at therapeutic concentrations [1] - It had no effect on ET_B-mediated signaling in human bronchial epithelial cells at concentrations up to 100 μM [2] |
| ln Vivo |
Sitaxsentan (5 mg/kg infused iv 10 min prior to onset of hypoxia) totally prevents hypoxia-induced vasoconstriction, and there is no difference in this group from the air controls. If rats are exposed to normal oxygen levels, the administration of sitaxsentan has no effect on MPAP; however, oral administration of sitaxsentan significantly reduces the increase in MPAP[2]. Sitaxentan by itself reduces the rise in MT brought on by shunts. While this remodeling is more successfully prevented when sitaxentan and sildenafil are taken together, it still tends to remain elevated when compared to controls[3].
In rats with monocrotaline-induced pulmonary arterial hypertension (PAH), oral Sitaxentan sodium (10-30 mg/kg/day for 21 days) dose-dependently reduced mean pulmonary arterial pressure (mPAP) by 25-40% and attenuated right ventricular hypertrophy (RVHI reduced by 30-50%) [2] - In pigs with overcirculation-induced PAH, Sitaxentan sodium (10 mg/kg/day, p.o.) combined with sildenafil (1 mg/kg/day, p.o.) reduced mPAP by 35% and improved cardiac output by 20%, showing synergistic efficacy [3] - In PAH rats, Sitaxentan sodium (30 mg/kg/day) inhibited pulmonary vascular remodeling, reducing medial wall thickness of pulmonary arteries by 45% [2] |
| Enzyme Assay |
Binding studies are conducted using 2 mg/tube (ETA) or 0.75 mg/tube (ETB) membrane in a 30 mM HEPES buffer, pH 7.4, with 150 mM NaCl, 5 mM MgCl2, and 0.05% bacitracin. A final concentration of 0.25% DMSO is obtained by dissolving sitaxentan sodium in DMSO and diluting it with the assay buffer. In a final volume of 200 μL containing 4 pM [125I]ET-1 (1.6 nCi), competitive inhibition experiments are carried out in triplicate. In the presence of 100 nM ET-1, nonspecific binding is found. Samples are incubated for 16 hours−18 hours at 24 °C. After adding one milliliter of PBS, the experiment is centrifuged at 2000 g for 25 minutes at 4 °C. On a Genesys gamma counter, the membrane-bound radioactivity is counted after the supernatant has been decanted.
ET_A/ET_B receptor binding assay: Membrane preparations from human ET_A/ET_B-expressing CHO cells were incubated with [¹²⁵I]-ET-1 (0.1 nM) and Sitaxentan sodium (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 [2] - Calcium mobilization assay: ET_A-CHO cells were loaded with calcium-sensitive dye, pretreated with Sitaxentan sodium (0.01-100 nM) for 20 minutes, then stimulated with ET-1 (10 nM). Calcium fluorescence intensity was monitored by fluorometry to assess receptor inhibition [2] |
| Cell Assay |
Transfected COS or TE 671 In six-well plates, seven cells are grown to confluence. Two milliliters of inositol-free RPMI-164 (IF-RPMI) media, containing two milliliters of [3H]myoinositol and ten percent inositol-free FCS, are added to each well's media sixteen hours before use. The wells are then incubated at 37 °C with 6% CO2. The cells undergo two PBS washes after the medium is aspirated. One milliliter of lithium buffer (15 μM HEPES, pH 7.4, 145 μM NaCl, 5.4 μM KCl, 1.8 μM CaCl2, 0.8 μM MgSO4, 1.0 μM NaH2PO4, 11.2 μM glucose, 20 μM LiCl) with or without sitaxentan sodium is used to preincubate cells for ten minutes before adding 100 μM of ET-1 at various concentrations. After that, the cells are incubated for a further forty-five minutes. The accumulated inositol phosphates are extracted using ice-cold methanol after the buffer is thrown away. After solubilizing the cells in 0.1 M NaOH, the total protein content of each well is determined using the BCA assay.
PASMC proliferation assay: Human PASMCs were seeded in 96-well plates, pretreated with Sitaxentan sodium (1-10 μM) for 1 hour, then stimulated with ET-1 (10 nM) for 72 hours. Cell proliferation was measured by BrdU incorporation assay [2] - Hepatobiliary transporter assay: Sandwich-cultured human hepatocytes were incubated with Sitaxentan sodium (1-50 μM) for 2 hours. Transporter-mediated uptake and efflux were quantified by LC-MS/MS to assess substrate properties [1] - Collagen synthesis assay: Human PASMCs were treated with Sitaxentan sodium (1-10 μM) plus ET-1 (10 nM) for 48 hours. Collagen production was quantified by Sircol dye binding assay [2] |
| Animal Protocol |
Sitaxsentan (15 or 30 mg/kg body weight per day in the drinking water) is given for 4 weeks during continuous exposure to hypoxia following an initial 2-week period of hypoxic exposure (10% O2). Following the four weeks of hypoxia, measurements of MPAP, MSAP, and HR are taken along with femoral and pulmonary arterial cannulation.
Monocrotaline-induced PAH rat model: Male Sprague-Dawley rats (200-250 g) were injected with monocrotaline (60 mg/kg, i.p.) to induce PAH. Sitaxentan sodium suspended in 0.5% CMC-Na was administered orally at 10, 20, 30 mg/kg/day from day 7 post-monocrotaline injection for 21 days. mPAP, RVHI, and pulmonary vascular remodeling were evaluated [2] - Overcirculation-induced PAH pig model: Female pigs (20-25 kg) underwent surgical shunt to induce PAH. Sitaxentan sodium (10 mg/kg/day) and sildenafil (1 mg/kg/day) were administered orally in combination for 4 weeks. Hemodynamic parameters (mPAP, cardiac output) were measured by cardiac catheterization [3] |
| ADME/Pharmacokinetics |
Oral bioavailability: Approximately 80% in rats after oral administration; approximately 75% in dogs after oral administration [2]
- Elimination half-life: 8.5 hours in rats; 11.2 hours in dogs [2] - Plasma protein binding: 97-99% in human plasma (concentration range: 0.1-10 μg/mL) [2] - Distribution: Volume of distribution (Vd) in rats = 1.2 L/kg, mainly distributed in lung and vascular tissues [2] - Metabolism: Metabolized in the liver via glucuronidation; no significant CYP450-mediated metabolism [1] - Excretion: 65-70% of the dose is excreted in feces as metabolites; 25-30% is excreted in urine; <5% is excreted unchanged [2] |
| Toxicity/Toxicokinetics |
Acute toxicity: oral LD50 in rats > 500 mg/kg; in mice > 400 mg/kg [2]
- Subchronic toxicity (oral administration in rats over 28 days): no significant hepatotoxicity or nephrotoxicity was observed at doses up to 30 mg/kg/day; liver transaminases were slightly elevated (≤2-fold) at 100 mg/kg/day [2] - No significant cytotoxicity was observed at concentrations up to 50 μM in sandwich-cultured human hepatocytes [1] - Drug interactions: no significant inhibition of CYP450 enzymes was observed; interactions with other hepatobiliary transport substrates (e.g., statins) are possible [1] |
| References |
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| Additional Infomation |
Drug Indication
Treatment of patients with pulmonary arterial hypertension (PAH) in WHO functional class III to improve their exercise capacity. Sitassentan sodium (sitassentan; IPI 1040) has been shown to be effective for primary pulmonary arterial hypertension and connective tissue disease-related pulmonary arterial hypertension. Sitassentan sodium is a potent, highly selective ET_A receptor antagonist used to treat pulmonary arterial hypertension (PAH) [2][3]. Its core mechanism is to block the binding of ET-1 to the ET_A receptor, thereby inhibiting downstream signaling pathways (calcium mobilization, MAPK) involved in vascular smooth muscle proliferation, vascular remodeling and hypertrophy [2]. Its therapeutic applications include reducing pulmonary artery pressure and right ventricular hypertrophy in patients with pulmonary arterial hypertension, and it has a synergistic effect when used in combination with phosphodiesterase 5 inhibitors (such as sildenafil) [3]. The high selectivity for the ET_A receptor rather than the ET_B receptor minimizes the side effects associated with the non-selective endothelin receptor. Antagonists, such as edema and gastrointestinal disturbances [2] - are substrates of hepatobiliary transporters, which may affect their hepatic distribution and potential drug interactions [1] |
| Molecular Formula |
C18H14CLN2NAO6S2
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| Molecular Weight |
476.89
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| Exact Mass |
475.988
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| Elemental Analysis |
C, 45.34; H, 2.96; Cl, 7.43; N, 5.87; Na, 4.82; O, 20.13; S, 13.45
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| CAS # |
210421-74-2
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| Related CAS # |
Sitaxsentan; 184036-34-8
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| PubChem CID |
11477084
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
726
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(C([H])([H])[H])=NOC=1[N-]S(C1C([H])=C([H])SC=1C(C([H])([H])C1=C([H])C2=C(C([H])=C1C([H])([H])[H])OC([H])([H])O2)=O)(=O)=O.[Na+]
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| InChi Key |
MDTNUYUCUYPIHE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H14ClN2O6S2.Na/c1-9-5-13-14(26-8-25-13)7-11(9)6-12(22)17-15(3-4-28-17)29(23,24)21-18-16(19)10(2)20-27-18;/h3-5,7H,6,8H2,1-2H3;/q-1;+1
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| Chemical Name |
sodium;(4-chloro-3-methyl-1,2-oxazol-5-yl)-[2-[2-(6-methyl-1,3-benzodioxol-5-yl)acetyl]thiophen-3-yl]sulfonylazanide
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| Synonyms |
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| 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 (5.24 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 (5.24 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: 33.33 mg/mL (69.89 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0969 mL | 10.4846 mL | 20.9692 mL | |
| 5 mM | 0.4194 mL | 2.0969 mL | 4.1938 mL | |
| 10 mM | 0.2097 mL | 1.0485 mL | 2.0969 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 |
| NCT00810732 | Completed | Drug: Open Drug: Nifedipine Drug: Placebo |
Chronic Kidney Disease | Pfizer | May 9, 2007 | Phase 2 |
| NCT00744211 | Completed | Other: Vehicle Drug: 1mg/kg sitaxsentan sodium |
Heart Disease | VA Office of Research and Development |
July 2008 | Not Applicable |
| NCT00303498 | Completed | Drug: Sitexsentin sodium Drug: Placebo |
Diastolic Heart Failure | Pfizer | June 2007 | Phase 2 |
| NCT00080457 | Completed | Drug: sitaxsentan sodium | Pulmonary Hypertension | Encysive Pharmaceuticals | May 2003 | Phase 3 |
| NCT01445873 | Completed | Drug: Sitaxentan sodium/ Placebo |
Healthy | Pfizer | September 2009 | Phase 1 |
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