Sitaxentan sodium (Sitaxsentan; IPI 1040)

Alias: IPI-1040; TBC11251;IPI1040; TBC-11251; IPI 1040; TBC 11251; TBC-11251 sodium salt; Sitaxsentan; Thelin; Sitaxentan sodium
Cat No.:V1511 Purity: ≥98%
Sitaxentan sodium (formerly IPI-1040; TBC-11251; IPI 1040; TBC11251; Thelin), the sodium salt ofSitaxentan, is a selective and orally bioavailable endothelin A receptor (ETA) antagonist with anti-hypertensive activity.
Sitaxentan sodium (Sitaxsentan; IPI 1040) Chemical Structure CAS No.: 210421-74-2
Product category: Endothelin Receptor
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Sitaxentan sodium (Sitaxsentan; IPI 1040):

  • Sitaxsentan (IPI 1040; TBC-11251)
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

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.

Biological Activity I Assay Protocols (From Reference)
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].

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].
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.
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.
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.
References

[1]. Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes. Can J Physiol Pharmacol. 2010 Jun;88.

[2]. Attenuation of pulmonary vascular hypertension and cardiac hypertrophy with sitaxsentan sodium, an orally active ET(A) receptor antagonist. Pulm Pharmacol Ther. 2000;13(2):87-97.

[3]. Sildenafil added to sitaxsentan in overcirculation-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol. 2010 Oct;299(4):H1118-23. Epub 2010 Aug 6.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C18H14CLN2NAO6S2
Molecular Weight
476.89
Exact Mass
475.99
Elemental Analysis
C, 45.34; H, 2.96; Cl, 7.43; N, 5.87; Na, 4.82; O, 20.13; S, 13.45
CAS #
210421-74-2
Appearance
Solid powder
SMILES
CC1=CC2=C(C=C1CC(=O)C3=C(C=CS3)S(=O)(=O)[N-]C4=C(C(=NO4)C)Cl)OCO2.[Na+]
InChi Key
MDTNUYUCUYPIHE-UHFFFAOYSA-N
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
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
Synonyms
IPI-1040; TBC11251;IPI1040; TBC-11251; IPI 1040; TBC 11251; TBC-11251 sodium salt; Sitaxsentan; Thelin; Sitaxentan sodium
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 Data
Solubility (In Vitro)
DMSO: 40~100 mg/mL (83.9~209.7 mM)
Water: <1 mg/mL
Ethanol: ~20 mg/mL (~41.9 mM)
Solubility (In Vivo)

Name: sodium (4-chloro-3-methylisoxazol-5-yl)((2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)thiophen-3-yl)sulfonyl)amide

InChi Key: MDTNUYUCUYPIHE-UHFFFAOYSA-N

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

SMILES Code: O=C(C(SC=C1)=C1S(N([Na])C2=C(C(C)=NO2)Cl)(=O)=O)CC3=C(C)C=C(OCO4)C4=C3

 (Please use freshly prepared in vivo formulations for optimal results.)
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.

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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.

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Clinical Trial Information
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
Biological Data
  • The effect of ambrisentan, darusentan, bosentan, and sitaxsentan on the sodium-dependent taurocholate cotransporter (NTCP)-mediated uptake of taurocholate in human hepatocytes. Data are means ± SD. Can J Physiol Pharmacol . 2010 Jun;88(6):682-91.
  • The effect of ambrisentan, darusentan, bosentan, and sitaxsentan on the organic anion transporter (OATP)-mediated uptake (intracellular accumulation) of estradiol-17β-d-glucuronide (E2-17βG) in human hepatocytes. Can J Physiol Pharmacol . 2010 Jun;88(6):682-91.
  • Means ± SE of medial thickness (%MT) expressed as percentage of external diameter of sham-operated, placebo-, sitaxsentan-, and sitaxsentan combined with sildenafil-treated piglets. Am J Physiol Heart Circ Physiol . 2010 Oct;299(4):H1118-23.
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