Among endothelin receptor antagonists, Sitaxentan sodium CAS 210421-74-2 stands out for the scale of its subtype selectivity: it blocks the ETA receptor at an IC50 of 1.4 nM while requiring roughly 7000 times that concentration to act on ETB. The compound traveled through development under the names TBC-11251 and IPI 1040 before reaching the market as Thelin for pulmonary arterial hypertension, a product later pulled due to liver toxicity findings. The Sitaxentan sodium molecular weight comes to 476.9 Da. The Sitaxentan sodium molecular structure pairs an isoxazole-sulfonamide unit with a benzodioxole acetyl side chain; in its sodium salt form, the Sitaxentan sodium chemical structure (also known by the code PF-01228305) dissolves readily in both water and DMSO, a practical feature for assay preparation.
Application of Sitaxentan sodium
Researchers reach for Sitaxentan sodium specifically when they need to isolate ETA-driven effects from the broader endothelin signaling network, since ETB activation produces largely opposite outcomes - nitric oxide release and receptor-mediated clearance of circulating endothelin. The compound's selectivity margin means the Sitaxentan sodium structure delivers a sharper experimental signal than older, non-selective endothelin antagonists whenever a study hinges on distinguishing ETA-specific vasoconstriction or cell proliferation from ETB activity. That property has kept it in active use across pulmonary hypertension models, vascular remodeling work, and fibrosis research tied to endothelin signaling.
In Vitro
Cell-based work in COS-7 cells confirmed that sitaxentan does more than occupy the receptor - it blocks the downstream signal, suppressing endothelin-1-triggered phosphoinositol hydrolysis with a pA2 value of 8. A separate phosphoinositide turnover assay produced a Ki of 0.69 nM, closely tracking the potency seen in direct binding studies. The agreement between these functional and binding measurements across independent laboratories is what makes the published IC50 trustworthy as a true reflection of receptor antagonism rather than a quirk of one particular assay design.
In Vivo
Rats subjected to acute hypoxia developed pulmonary hypertension that sitaxentan reversed at an ED50 of 0.5 mg/kg, and in a separate mouse model of arterial injury, the compound limited the resulting neointimal lesion - evidence that ETA blockade curbs vascular smooth muscle growth even apart from its blood pressure effects. Lung injury induced by bleomycin in mice responded similarly: a 15 mg/kg dose of sitaxentan cut bronchoalveolar pleocytosis, reduced collagen buildup, limited fibrotic changes, and left animals with better lung mechanics overall. Extending the dosing to 28 days in a chronic wire-injury model produced the same antiproliferative outcome in femoral arteries, confirming the effect holds up beyond single-dose experiments.
Biochemical and Physiological Actions
At the receptor level, sitaxentan works by competing directly with endothelin-1 for the ETA binding site on vascular smooth muscle, which shuts down the vasoconstriction and proliferative signaling that ET-1 would otherwise trigger. The physiological logic behind targeting ETA specifically comes from how differently the two endothelin receptor subtypes behave: ETA promotes constriction and cell growth, while ETB leans toward vasodilation and endothelin removal from circulation. Selective ETA blockade therefore lets a researcher shut down the pathological signaling arm without disturbing the protective functions that ETB provides.
Features and Benefits of Sitaxentan sodium
What makes Sitaxentan sodium (CAS 210421-74-2) valuable as a laboratory tool is the combination of sub-nanomolar receptor affinity with a selectivity margin rarely matched among endothelin antagonists, a profile verified independently through both binding and functional assays. Add to that its oral activity and a track record spanning pulmonary hypertension, vascular injury, and fibrosis models, and the result is a compound with substantial experimental breadth. Its withdrawal from clinical use has not diminished that research value - if anything, its well-documented pharmacology now serves as a comparison point for newer endothelin receptor antagonists entering development.
