Sitaxentan

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Chemical compound

title: "Sitaxentan" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["benzodioxoles", "chloroarenes", "endothelin-receptor-antagonists", "hepatotoxins", "isoxazoles", "sulfonamides", "thiophenes", "withdrawn-drugs"] description: "Chemical compound" topic_path: "general/benzodioxoles" source: "https://en.wikipedia.org/wiki/Sitaxentan" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Chemical compound ::

::data[format=table title="Infobox drug"]

Field	Value
IUPAC_name	N-(4-chloro-3-methyl-5-isoxazolyl)-2-[[4,5-(methylenedioxy)-o-tolyl]acetyl]-3-thiophenesulfonamide
image	Sitaxentan.svg
image_class	skin-invert-image
width	225
Drugs.com
licence_EU	yes
pregnancy_AU
pregnancy_US
INN_EMA	sitaxentan sodium
legal_CA
legal_US
legal_status	Withdrawn
routes_of_administration	Oral
bioavailability	70 to 100%
protein_bound	99%
metabolism	Hepatic (CYP2C9- and CYP3A4-mediated)
elimination_half-life	10 hours
excretion	Renal (50 to 60%)
Fecal (40 to 50%)
CAS_number	184036-34-8
CAS_supplemental
210421-64-0 (sodium salt)
ATC_prefix	C02
ATC_suffix	KX03
PubChem	216235
IUPHAR_ligand	3950
DrugBank	DB06268
ChemSpiderID	21106381
UNII_Ref
UNII	J9QH779MEM
KEGG	D07171
ChEMBL	282724
C	18
smiles	Cc1cc2OCOc2cc1CC(=O)c3sccc3S(=O)(=O)Nc4onc(C)c4Cl
synonyms	TBC-11251
::

| IUPAC_name = N-(4-chloro-3-methyl-5-isoxazolyl)-2-[[4,5-(methylenedioxy)-o-tolyl]acetyl]-3-thiophenesulfonamide | image = Sitaxentan.svg | image_class = skin-invert-image | width = 225

| C=18 | H=15 | Cl=1 | N=2 | O=6 | S=2 | smiles = Cc1cc2OCOc2cc1CC(=O)c3sccc3S(=O)(=O)Nc4onc(C)c4Cl | synonyms = TBC-11251

Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH). It was marketed as Thelin by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity.

Mechanism of action

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). It is a sulfonamide class endothelin receptor antagonist (ERA) and is undergoing Food and Drug Administration (FDA) review for treating pulmonary hypertension. The rationale for benefit compared with bosentan, a nonselective ET blocker, is negligible inhibition of the beneficial effects of ETB stimulation, such as nitric oxide production and clearance of ET from circulation. In clinical trials, the efficacy of sitaxentan has been much the same as bosentan, but the hepatotoxicity of sitaxentan outweighs its benefits. Dosing is once daily, as opposed to twice daily for bosentan.

Regulatory status

On December 10, 2010 Pfizer announced it would be withdrawing sitaxentan worldwide (both from marketing and from all clinical study use), citing that it is a cause of fatal liver damage.

Sitaxentan was approved for marketing in the European Union in 2006, in Canada in 2006 and in Australia in 2007. By February 2008 it had been launched commercially in Germany, Austria, The Netherlands, the United Kingdom, Ireland, France, Spain and Italy.

In March 2006, the FDA recommended an approvable status to sitaxentan but said it would not yet approve the product. In July 2006, sitaxentan received a second approvable letter stating that efficacy outcome issues raised in the context of the STRIDE-2 study were still unresolved. In July 2007, Encysive commenced a formal dispute resolution process in a preliminary meeting with the FDA. In September 2007 the company announced that it was making preparations for another phase III clinical trial (intended to be named STRIDE-5) to overcome the FDA's concerns. The takeover by Pfizer resulted in a reconfiguration and extension of these plans, to include combination therapy with sildenafil. The Sitaxentan Efficacy and Safety Trial With a Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) was an ongoing program of three clinical trials conducted in the United States (ClinicalTtrials.gov identifiers: NCT00795639, NCT00796666 and NCT00796510) with anticipated completion dates between June 2010 and January 2014.

Adverse effects

Adverse effects observed with sitaxentan are class effects of endothelin receptor antagonists, and include :

liver enzyme abnormalities (increased ALT and AST)
headache
edema
constipation
nasal congestion
upper respiratory tract infection
dizziness
insomnia
flushing

Because sitaxentan inhibits metabolism of warfarin, a decreased dose of warfarin is needed when co-administered with sitaxentan. This is because warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.

References

(February 2004). "Sitaxsentan therapy for pulmonary arterial hypertension". American Journal of Respiratory and Critical Care Medicine.
(2010-12-10). "Citing Liver Damage, Pfizer Withdraws Thelin - CBS Detroit".
(November 2007). "Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease". Annals of the Rheumatic Diseases.
(30 May 2007). "UPDATE 1-Encysive gets Canadian approval for hypertension drug". Reuters.
(29 September 2007). "Encysive Pharmaceuticals to Conduct Phase III Study With Thelin (Sitaxsentan Sodium) in Pulmonary Arterial Hypertension". PrimeNewswire via COMTEX News Network.

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