Bosentan | 147536-97-8, Bosentan Formula

Description

Pale Yellow to Off-White SolidBosentan was introduced in the US as a twice-daily oral treatment for pulmonary arterial hypertension. It can be synthesized in five steps via condensation of diethyl (2- methoxyphenoxy)malonate with pyrimidine-2-carboxamidine to give the precursor of the symmetrical central dichloropyrimidine ring which is then successively treated with the potassium salt of 4-tert-butylbenzenesulfonamide and the sodium salt of ethylene gycol. Bosentan is the first endothelin

Solid

Bosentan is a sulfonamide, a member of pyrimidines and a primary alcohol. It has a role as an antihypertensive agent and an endothelin receptor antagonist.|Bosentan is a dual endothelin receptor antagonist marketed under the trade name Tracleer by Actelion Pharmaceuticals. Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure.|Bosentan anhydrous is an Endothelin Receptor Antagonist. The mechanism of action of bosentan anhydrous is as an Endothelin Receptor Antagonist, and Cytochrome P450 3A Inducer, and Cytochrome P450 2C9 Inducer.|Bosentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Bosentan has been associated with serum enzyme elevations during therapy and with rare instances of clinically apparent acute liver injury.|A sulfonamide and pyrimidine derivative that acts as a dual endothelin receptor antagonist used to manage PULMONARY HYPERTENSION and SYSTEMIC SCLEROSIS.

Bosentan Basic Attributes

Molecular Weight：

551.61

Exact Mass：

551.61

EC Number：

1308068-626-2

UNII：

XUL93R30K2

DSSTox ID：

DTXSID7046627

ATC Code：

C02KX01|C - Cardiovascular system

HScode：

29350090

Characteristics

PSA：

154

XLogP3：

3.7

Appearance：

Pale Yellow to Off-White Solid

Density：

1.325±0.06 g/cm3(Predicted)

Melting Point：

107-110°C

Boiling Point：

742.3±70.0 °C(Predicted)

Flash Point：

402.8±35.7 °C

Refractive Index：

1.607

Water Solubility：

Poorly soluble in water (1.0 mg/100 ml) and in aqueous solutions at low pH (0.1 mg/100 ml at pH 1.1 and 4.0; 0.2 mg/100 ml at pH 5.0). Solubility increases at higher pH values (43 mg/100 ml at pH 7.5).

Storage Conditions：

-20°C Freezer

Vapor Pressure：

0mmHg at 25°C

Safety Information

wgk germany：

3

hazard class code：

R36:Irritating to the eyes. R43:May cause sensitization by skin contact.

safety instructions：

S26-S36/37-S24/25-S22

Marks：

Xi

Precautionary statement(s)：

P201, P202, P273, P281, P308+P313, P405, P501

Hazard Statements：

H360

GHS Classification：

|Danger|H302 (33.33%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P273, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 3 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Toxicity

Toxicity Summary：

Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

Hepatotoxicity：

Bosentan is associated with elevations in serum aminotransferase levels above three times the upper limit of the normal range (ULN) in 3% to 18% of patients, averaging 7.6% using currently recommended doses. The enzyme elevations are usually self-limited and are rarely accompanied by symptoms, but can be more marked and persist and require dose reduction or discontinuation (in 3% to 4% of patients). Monthly monitoring of serum aminotransferase levels is recommended, with discontinuation for levels above 8 times the ULN or for values above 5 times the ULN that persist. There have also been rare reports of clinically apparent liver injury with jaundice associated with bosentan use. The onset of illness was usually within 1 to 6 months of starting bosentan, but cases arising during chronic therapy have also been described (Case 1). The enzyme pattern has typically been hepatocellular or mixed. Immunoallergic features are usually not present and autoantibodies are usually absent or present in low titer. Some cases have been severe and fatalities have been reported, but there have been no published reports of chronic hepatitis or vanishing bile duct syndrome attributed to bosentan. Autoimmune and immunoallergic features are usually not present.

Protein Binding：

Greater than 98% to plasma proteins, mainly albumin.

Drug Information

Drug Indication：

Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).|FDA Label|Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III.Efficacy has been shown in:Primary (idiopathic and familial) PAH;PAH secondary to scleroderma without significant interstitial pulmonary disease;PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology.Some improvements have also been shown in patients with PAH WHO functional class II.Tracleer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.|Treatment of interstitial pulmonary fibrosis, Treatment of pulmonary arterial hypertension, Treatment of systemic sclerosis

LiverTox Summary：

Bosentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Bosentan has been associated with serum enzyme elevations during therapy and with rare instances of clinically apparent acute liver injury.

Drug Classes：

Pulmonary Arterial Hypertension Agents

Pharmacology：

Bosentan 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. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

MeSH：

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)|Compounds and drugs that bind to and inhibit or block the activation of ENDOTHELIN RECECPTORS. (See all compounds classified as Endothelin Receptor Antagonists.)

Absorption：

Absolute bioavailability is approximately 50% and food does not affect absorption.|Bosentan is eliminated by biliary excretion following metabolism in the liver.|18 L|4 L/h [patients with pulmonary arterial hypertension]

Metabolism/Metabolites：

Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.|Bosentan has known human metabolites that include 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-hydroxyphenoxy)-[2,2-]bipyrimidinyl-4-yl]-benzenesulfonamide and Hydroxy Bosentan.

Biological Half-Life：

Terminal elimination half-life is about 5 hours in healthy adult subjects.

Mechanism of Action：

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET_A and ET_B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET_A receptors than ET_B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET_A and ET_B.

MeSH Entry Terms：

4-t-butyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide

Bosentan Use and Manufacturing

Uses

A mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.

Use Classification：

Human drugs -> Tracleer -> EMA Drug Category|Antihypertensives -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

Computed Properties

Molecular Weight:551.6
XLogP3:3.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:11
Rotatable Bond Count:11
Exact Mass:551.18385484
Monoisotopic Mass:551.18385484
Topological Polar Surface Area:154
Heavy Atom Count:39
Complexity:839
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

Drug Function and Efficacy

This product is a dual endothelin receptor antagonist with affinity for ETA and ETB receptors. Bosentan can reduce pulmonary and systemic vascular resistance, thereby increasing cardiac output without increasing heart rate. By competing with ETA and ETB receptors, it reduces pulmonary vascular resistance, reverses pulmonary vascular and right ventricular hypertrophy, and also shows the effect of reducing collagen deposition in animal models.

This ingredient has been used in drugs with the following functions (note: it does not mean that the ingredient itself has the following health functions)

Related Drugs

Bosentan Tablets
Ingredients	Chemical name: 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methyl-phenoxy)-[2,2]-dipyrimidin-4-yl]-phenylsulfonamide monohydrate
Indication	Cytochrome P450 system: Bosentan has no relevant inhibitory effect on the cytochrome P450 isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6. Bosentan does not increase the plasma concentrations of drugs metabolized by these enzymes. Bosentan is a mild to moderate inducer of CYP3A4 and CYP2C9. Plasma concentrations of drugs metabolized by these 2 enzymes may be reduced when Bosentan is used concomitantly. Warfarin: Concomitant use of Bosentan, 500 mg twice daily, can reduce the plasma concentrations of S-warfarin and R-warfarin by approximately 30%. Patients with pulmonary hypertension receiving long-term warfarin therapy took Bosentan 125 mg, b.i.d., and there was no clinically significant effect on clotting time/INR. No additional dose adjustment of warfarin is required, but regular INR monitoring is recommended. Simvastatin and other statins: Concomitant use of this product reduces the plasma concentration of simvastatin and its major active beta-hydroxy acid metabolite by approximately 50%. Plasma concentrations of this product are not affected. This product also reduces the plasma concentrations of other statins that are mainly metabolized by CYP3A4. For these statins, a decrease in statin efficacy must be considered. Glyburide: The risk of elevated transaminases has been observed in patients receiving concomitant treatment with glyburide. Therefore, the combined use of this product and glyburide is contraindicated and alternative hypoglycemic agents should be considered (see Contraindications). Concomitant use of this product can reduce the plasma concentration of glyburide by approximately 40%. The plasma concentration of this product is also reduced by 30%. This product may also reduce the plasma concentration of other hypoglycemic drugs that are mainly metabolized by CYP2C9 and CYP3A4. In patients using these drugs, the possibility of loss of glycemic control must be considered. Ketoconazole: Concomitant use of this product and ketoconazole can increase the plasma concentration of this product by approximately 2 times. No dose adjustment is required, but an increased effect of this product should be considered. Nimodipine, digoxin, losartan: There is no pharmacokinetic interaction between this product and digoxin and nimodipine. Losartan has no effect on the plasma level of this product. Cyclosporine A: Concomitant use of this product can reduce the concentration of cyclosporine A in the blood by about 50%. The initial trough concentration of this product when used in combination is about 30 times higher than when used alone. However, at steady state, the plasma concentration of this product is only 3-4 times higher. The combination of this product and cyclosporine A is prohibited. No drug interaction studies have been conducted on tacrolimus, but similar interactions can be expected. It is recommended to avoid the concomitant use of this product and tacrolimus. Hormonal contraceptives: No specific interaction studies with oral, injectable or implantable contraceptives have been conducted. Many of these drugs are metabolized by CYP3A4 and there is a possibility of contraceptive failure when used in combination with this product. Therefore, an additional or alternative contraceptive method should be used.
Specifications	125 mg (based on C27H29N5O6 tablets)

Bosentan Tablets
Ingredients	Chemical name: 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidin-4-yl]-benzenesulfonamide monohydrate Molecular formula: C27H29N5O6S.H2O Molecular weight: 569.64
Indication	none
Specifications	125 mg (based on C27H29N5O6 tablets)

Bosentan Tablets
Ingredients	Chemical name: 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methyl-phenoxy)-[2,2]-dipyrimidin-4-yl]-phenylsulfonamide monohydrate
Indication	Cytochrome P450 system: Bosentan has no relevant inhibitory effect on the cytochrome P450 isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19 and CYP2D6. Bosentan does not increase the plasma concentrations of drugs metabolized by these enzymes. Bosentan is a mild to moderate inducer of CYP3A4 and CYP2C9. Plasma concentrations of drugs metabolized by these 2 enzymes may be reduced when Bosentan is used concomitantly. Warfarin: Concomitant use of Bosentan, 500 mg twice daily, can reduce the plasma concentrations of S-warfarin and R-warfarin by approximately 30%. Patients with pulmonary hypertension receiving long-term warfarin therapy took Bosentan 125 mg, b.i.d., and there was no clinically significant effect on clotting time/INR. No additional dose adjustment of warfarin is required, but regular INR monitoring is recommended. Simvastatin and other statins: Concomitant use of this product reduces the plasma concentration of simvastatin and its major active beta-hydroxy acid metabolite by approximately 50%. Plasma concentrations of this product are not affected. This product also reduces the plasma concentrations of other statins that are mainly metabolized by CYP3A4. For these statins, a decrease in statin efficacy must be considered. Glyburide: The risk of elevated transaminases has been observed in patients receiving concomitant treatment with glyburide. Therefore, the combined use of this product and glyburide is contraindicated and alternative hypoglycemic agents should be considered (see Contraindications). Concomitant use of this product can reduce the plasma concentration of glyburide by approximately 40%. The plasma concentration of this product is also reduced by 30%. This product may also reduce the plasma concentration of other hypoglycemic drugs that are mainly metabolized by CYP2C9 and CYP3A4. In patients using these drugs, the possibility of loss of glycemic control must be considered. Ketoconazole: Concomitant use of this product and ketoconazole can increase the plasma concentration of this product by approximately 2 times. No dose adjustment is required, but an increased effect of this product should be considered. Nimodipine, digoxin, losartan: There is no pharmacokinetic interaction between this product and digoxin and nimodipine. Losartan has no effect on the plasma level of this product. Cyclosporine A: Concomitant use of this product can reduce the concentration of cyclosporine A in the blood by about 50%. The initial trough concentration of this product when used in combination is about 30 times higher than when used alone. However, at steady state, the plasma concentration of this product is only 3-4 times higher. The combination of this product and cyclosporine A is prohibited. No drug interaction studies have been conducted on tacrolimus, but similar interactions can be expected. It is recommended to avoid the concomitant use of this product and tacrolimus. Hormonal contraceptives: No specific interaction studies with oral, injectable or implantable contraceptives have been conducted. Many of these drugs are metabolized by CYP3A4 and there is a possibility of contraceptive failure when used in combination with this product. Therefore, an additional or alternative contraceptive method should be used.
Specifications	62.5 mg (based on C27H29N5O6 tablets)

Registered Holders

ALIVUS LIFE SCIENCES LTD

United States
Active
MATRIX PHARMACORP PRIVATE LTD

United States
Active
ALEMBIC PHARMACEUTICALS LTD

United States
Active

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