product name Sitaxentan sodium
Description: Sitaxentan sodium, also known as TBC-11251 and IPI 1040, is a selective endothelin A receptor (ETA) antagonist with IC50 and Ki of 1.4 nM and 0.43 nM, respectively, it exhibits 7000-fold selectivity over ETB. Sitaxentanis a medication for the treatment of pulmonary arterial hypertension (PAH). Sitaxentan is a small molecule that blocks the action of endothelin (ET) on the endothelin-A (ETA) receptor selectively (by a factor of 6000 compared with the ETB).
References: J Med Chem. 1997;40(11):1690-7; Pulm Pharmacol Ther. 2000;13(2):87-97; Neurosurgery. 1998;43(6):1409-17.
476.89
Formula
C18H14ClN2O6S2.Na
CAS No.
210421-74-2
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 40 mg/mL (83.9 mM)
Water: <1 mg/mL
Ethanol: 20 mg/mL (41.9 mM)
Solubility (In vivo)
Synonyms
TBC-11251
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19417195
| In Vitro |
In vitro activity: Sitaxentan sodium inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.69 nM and a pA2 of 8.0. Kinase Assay: Binding studies are performed in a 30 mM HEPES buffer, pH 7.4, containing 150 mM NaCl, 5 mM MgCl2, and 0.05% bacitracin using 2 mg/tube (ETA) or 0.75 mg/tube (ETB) membrane. Sitaxentan sodium is dissolved in DMSO and diluted with the assay buffer to give a final concentration of 0.25% DMSO. Competitive inhibition experiments are performed in triplicate in a final volume of 200 μL containing 4 pM [125I]ET-1 (1.6 nCi). Nonspecific binding is determined in the presence of 100 nM ET-1. Samples are incubated for 16 hours−18 hours at 24 °C. One milliliter of PBS is then added and the assay centrifuged at 2000 g for 25 minutes at 4 °C. The supernatant is decanted and the membrane bound radioactivity counted on a Genesys gamma counter. Cell Assay: TE 671 or transfected COS 7 cells are grown to confluence in six-well plates. Sixteen hours prior to use, the media in each well is replaced with 2 mL of inositol-free RPMI-164 (IF-RPMI) media containing 10% inositol-free FCS and 2 mCi [3H]myoinositol and incubated at 37 °C in the presence of 6% CO2. The media is aspirated, and the cells are washed twice with PBS. Cells are preincubated for 10 minutes in 1 mL 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 prior to the addition of 100 μM of ET-1 at different concentrations. Cells are then incubated for an additional 45 minutes. The buffer is discarded, and the accumulated inositol phosphates are extracted with ice cold methanol. The total cell protein in each well is measured using the BCA assay after solubilizing the cells in 0.1 M NaOH. |
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| In Vivo | Sitaxentan sodium has a serum half-life in the rat and the dog of 6 hours – 7 hours and 60−100% oral bioavailability. Orally administered Sitaxentan sodium is rapidly absorbed in both the rat and the dog with a t1/2(abs) of 0.7 hours and 0.3 hours, respectively. Peak plasma concentrations occurred between 2 hours and 3 hours postdosing in the rat and between 45 minutes and 90 minutes in the dog. The pulmonary vasoconstrictor response to acute hypoxia (10% O2 for 90 minutes) is prevented with Sitaxentan sodium (5 mg/kg infused i.v. 10 minutes prior to the onset of hypoxia). Sitaxentan sodium delivered i.v. 50 minutes after the onset of hypoxia reverses the established pulmonary vasoconstriction. Sitaxsentan blocks increased plasma endothelin levels. Sitaxsentan dose dependently (10 mg/kg and 50 mg/kg per day in the drinking water) attenuates right ventricular systolic pressure, right heart hypertrophy, and pulmonary vascular remodeling observed 3 weeks after a single subcutaneous injection of monocrotaline. Systemic administration of the ETA receptor antagonist Sitaxentan sodium significantly attenuates cerebral vasospasm after subarachnoid hemorrhage (SAH). Sitaxentan sodium reduces the development of hypoxic pulmonary vasoconstriction (HPV) in the pig. In addition, bolus injection of Sitaxentan sodium reverses already established HPV. |
| Animal model | |
| Formulation & Dosage | |
| References | J Med Chem. 1997 May 23;40(11):1690-7; Pulm Pharmacol Ther. 2000;13(2):87-97; Neurosurgery. 1998 Dec;43(6):1409-17; discussion 1417-8. |
