Sitaxsentan

TBC11251 (Sitaxsentan) Texas Biotechnology, USA ETA receptor Grade III PAH (designated orphan medicine in 2004)... 

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). ... 

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. 

Sitaxsentan is a potent and selective agent which inhibits ET-1 binding to ETA receptors (IC50 = 1.4 nM), while being essentially inactive at ETB receptors (IC50 = 9.8 pM).23 In the clinic, it was found to have excellent oral bioavailability (70-100%) and a terminal elimination half-life of 10 h, and is administered as a once daily 100 mg dose. It is highly protein bound in plasma (> 99%) and extensively metabolized in the liver to inactive metabolites, predominantly by CYPs 2C9 and 3A4. Excretion is 50 60% renal, with the balance in the feces.25 Sitaxsentan inhibits CYP 2C9, and was observed to increase exposure to warfarin by over twofold. The use of cyclosporine A is also contraindicated, but no interactions were observed with sildenafil.15 Sitaxsentan was well tolerated in trials, with only minor side effects reported. Reversible liver enzyme abnormalities were also observed, but less frequently than with bosentan.15 25... 

The structure of sitaxsentan (2) is also somewhat modular and was divided into three building blocks—namely the phenyl ring, the central thiophene, and the aminoisoxazole. The isoxazole subunit 33 can be prepared by the reaction of hydroxylamine with butynenitrile (31) to form the heterocycle,30 followed by chlorination with NCS.22 The thiophene ring can be formed using a Fiesselmann thiophene synthesis starting from... 

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. 

Synonym Sitaxsentan Trade name Thelin (Encysize)... 

FDHF01 Sitaxsentan PEFHF Target 150 Results pending n/a... 

The two FDA-approved ERA are bosentan and ambrisentan. Sitaxsentan is not approved in the United States although it has been approved in Europe, Canada, Australia, and Israel. 

Sitaxsentan is approved outside of the United Sates, is a more selective ETa receptor antagonist, and is also a once daily drug. It has significant interactions with warfarin and is more similar to ambrisentan with respect to incidence of transaminitis. A nonblinded, nonrandomized extension study suggested a more favorable response to sitaxsentan than bosentan in the CTD patient population (101). 

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. 

Liver Fulminant hepatic failure during treatment with sitaxsentan has been reported in a patient whose liver function tests had been normal less than a month before [86 ]. 

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