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Sitaxentan | CAS No: 184036-34-8 | GMP-certified suppliers
A medication that targets pulmonary arterial hypertension and related cardiovascular conditions by reducing vascular resistance and improving heart function with endothelin receptor antagonism.
Therapeutic categories
Primary indications
- Investigated for use/treatment in pulmonary hypertension, connective tissue diseases, hypertension, and congestive heart failure
Product Snapshot
- Sitaxentan is an oral small molecule available in film-coated tablet formulations
- It has been investigated for pulmonary hypertension, connective tissue diseases, hypertension, and congestive heart failure indications
- Sitaxentan is approved in Canada and the EU but has also been withdrawn and is investigational in other markets
Clinical Overview
Pharmacologically, sitaxentan is an endothelin receptor antagonist (ERA) that exhibits high affinity and competitive antagonism at endothelin-A (ET-A) receptors with lesser activity at endothelin-B (ET-B) receptors. Endothelin-1 is a potent vasoconstrictor elevated in patients with PAH; by selectively blocking ET-A receptors, sitaxentan reduces pulmonary vasoconstriction and vascular remodeling, lowering pulmonary arterial pressure. Its preferential binding to ET-A over ET-B is thought to contribute to its pharmacodynamic profile.
From an absorption, distribution, metabolism, and excretion (ADME) perspective, sitaxentan is metabolized primarily by cytochrome P450 enzymes, including CYP2C9 and CYP3A4 isoforms, and acts as an inhibitor of several CYP enzymes, notably CYP2C19, CYP2C9, and CYP3A4. These interactions may pose a risk for drug-drug interactions and warrant careful consideration during co-administration with other substrates of these enzymes.
Safety concerns with sitaxentan centered on hepatotoxicity, including cases of severe liver injury leading to market withdrawal. Other toxicity profiles include potential impacts on renal function and hematologic parameters. Because of the liver safety issues, regular hepatic monitoring would be essential in clinical contexts had the compound remained available.
While sitaxentan demonstrated clinical efficacy in PAH, the therapeutic class now predominantly employs other endothelin receptor antagonists with improved safety profiles. For API sourcing, procurement should prioritize manufacturer compliance with good manufacturing practices (GMP), thorough impurity profiling, and verification of chemical identity and potency. Given the compound’s sensitivity and history, engagement with suppliers able to provide detailed stability and safety documentation is critical for research or development purposes.
Identification & chemistry
| Generic name | Sitaxentan |
|---|---|
| Molecule type | Small molecule |
| CAS | 184036-34-8 |
| UNII | J9QH779MEM |
| DrugBank ID | DB06268 |
Pharmacology
| Summary | Sitaxentan is an endothelin receptor antagonist that competitively inhibits endothelin-1 binding primarily at endothelin-A (ET-A) receptors, with additional activity at endothelin-B (ET-B) receptors. By blocking endothelin-1 induced vasoconstriction, it reduces pulmonary vascular resistance. This mechanism targets elevated endothelin levels associated with pulmonary hypertension and related cardiovascular conditions. |
|---|---|
| Mechanism of action | Sitaxentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A or ET-B receptors causes pulmonary vasoconstriction. By blocking this interaction, Sitaxentan decreases pulmonary vascular resistance. Sitaxentan has a higher affinity for ET-A than ET-B. |
| Pharmacodynamics | 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. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Endothelin-1 receptor | Humans | antagonist |
| Endothelin B receptor | Humans | antagonist |
ADME / PK
| Absorption | 70-100% |
|---|---|
| Half-life | 10 hours |
| Protein binding | 99% + |
| Metabolism | Hepatic (CYP2C9- and CYP3A4-mediated) |
| Route of elimination | Renal (50 to 60%) Fecal (40 to 50%) |
Formulation & handling
- Sitaxentan is a small molecule intended for oral administration in tablet form with film coating.
- Due to low water solubility (1.81e-02 g/l) and moderate lipophilicity (LogP 3.09), formulation strategies should address dissolution and bioavailability.
- It is stable for oral handling and can be taken with or without food, indicating limited food interaction concerns.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is in the mature phase of its lifecycle, with key patents having expired in Canada between 2014 and 2018. The product is marketed in both the Canadian and European Union markets. |
|---|
| Markets | Canada, EU |
|---|
Supply Chain
| Supply chain summary | Sitaxentan is marketed primarily in Canada and the EU, with branded products under the name Thelin. The presence of multiple patents in Canada, expiring between 2014 and 2018, indicates that generic competition is either established or likely imminent in these markets. The supply landscape includes originator companies involved in initial production and brand distribution, with opportunities for generic manufacturers post-patent expiry. |
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Sitaxentan is a type of Other calcium Channel Blockers
Other calcium channel blockers are a category of pharmaceutical active pharmaceutical ingredients (APIs) that work by inhibiting the influx of calcium ions into cells through voltage-gated calcium channels. These medications are primarily used to treat various cardiovascular conditions, such as hypertension (high blood pressure) and angina (chest pain).
Unlike commonly known calcium channel blockers like dihydropyridines and non-dihydropyridines, other calcium channel blockers encompass a diverse group of drugs that possess calcium channel-blocking activity but may have different chemical structures and mechanisms of action.
These APIs exert their therapeutic effects by binding to specific calcium channels in cardiac and smooth muscle cells, reducing calcium entry and subsequent muscle contraction. By doing so, they relax blood vessels, improve blood flow, and reduce cardiac workload, resulting in lower blood pressure and alleviation of angina symptoms.
Some examples of other calcium channel blockers include bepridil, mibefradil, and verapamil. These drugs may have additional effects beyond calcium channel blockade, such as antiarrhythmic properties or interactions with other receptor systems.
As with any medication, other calcium channel blockers may have potential side effects, including dizziness, flushing, constipation, and peripheral edema. Therefore, it is important to use these drugs under the supervision of a healthcare professional and follow the prescribed dosage instructions.
In conclusion, other calcium channel blockers are a diverse class of pharmaceutical APIs that act by blocking calcium channels, leading to decreased blood pressure and relief from angina. These medications offer an alternative treatment option for cardiovascular conditions and should be used as directed by a healthcare provider to ensure safety and efficacy.
