N- (4- chloro- 3- methyl- oxazol- 5- yl)- 2- [2- (6- methylbenzo[1,3]dioxol- 5- yl)acetyl]- thiophene- 3- sulfonamide

Absorption

70-100%

Description

Sitaxsentan is a selective endothelin-A (ETA) receptor antagonist launched for the treatment of patients with pulmonary arterial hypertension (PAH), to improve exercise capacity. It is the second ET receptor antagonist to be marketed for this indication behind bosentan. PAH encompasses a heterogeneous group of disorders characterized by inappropriate overactivation of the endothelin system and is characterized by a progressive increase in pulmonary vascular resistance resulting from vascular remodeling, vasoconstriction, and cellular proliferation. Endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, is a key contributor to the acceleration of the disease, and its effects are mediated through activation of ETA and ETB receptors. ETA receptors are found primarily on smooth muscle cells and, when activated, induce vasoconstriction and cellular proliferation. ETB receptors are expressed in both pulmonary vascular endothelial cells and smooth muscle cells, and their activation is associated with the renal and pulmonary clearance of ET.

Originator

Encysive (US)

Indications

Investigated for use/treatment in pulmonary hypertension, connective tissue diseases, hypertension, and congestive heart failure.

Background

Sitaxentan was marketed under the trade name Thelin for the treatment of pulmonary arterial hypertension (PAH) by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market over concerns of hepatotoxicity.

Definition

ChEBI: Sitaxentan is a member of benzodioxoles.

brand name

Thelin

Pharmacokinetics

Sitaxentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Sitaxentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

Metabolism

Hepatic (CYP2C9- and CYP3A4-mediated)