Endothelin receptor antagonists sitaxsentan

Bosentan is a nonselective receptor blocker. It is active orally, and blocks both the initial transient depressor (ETB) and the prolonged pressor ( ) responses to intravenous endothelin. Many orally active endothelin receptor antagonists with increased selectivity have been developed and are available for research use. Examples include the selective antagonists sitaxsentan and ambrisentan. 

Liver The availability of ambrisentan in patients with pulmonary artery hypertension who have previously discontinued other endothelin receptor antagonists because of liver function abnormalities provides an important option for patients who have had adverse reactions to bosentan or sitaxsentan [76 ]. Ambrisentan is a... 

ETA-selective antagonists included a more selective (>25 000-fold) p)rrrolidine carboxylic acid derivatives A-216546 (121). A-216546 was orally available in rat, dog and monkey and blocked endothelin-1-induced presser response in conscious rats. Replacement of the dialkylacetamide side chain in 121 resulted in a complete reversal of receptor selectivity, preferring ETb over ET. Compound 122 (A-308165) demonstrated over 27 000-fold selectivity favouring the ETb receptor. So far one of the endothelin ETA-receptor antagonists bosentan (123) has reached the market for the treatment of pulmonary h)rpertension. Several other compounds have either failed in the clinic or are in various stages of development (e.g. sitaxsentan (124) and 125). ... 

Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarhn J. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension open-label pilot study. Chest 2002 121(6) 1860-8. 

Barst RJ, Langleben D, Badesch D, et al STRIDE-2 Study Group. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006 47(10) 2049-56. 

---