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| | Bosentan Basic information |
| | Bosentan Chemical Properties |
| Melting point | 107-110°C | | Boiling point | 742.3±70.0 °C(Predicted) | | density | 1.325±0.06 g/cm3(Predicted) | | storage temp. | -20°C Freezer | | solubility | DMSO (Slightly), Methanol (Slightly) | | pka | 4.01±0.10(Predicted) | | form | Solid | | color | White to Pale Yelloow | | CAS DataBase Reference | 147536-97-8(CAS DataBase Reference) |
| | Bosentan Usage And Synthesis |
| Description | Bosentan 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 (ET) receptor antagonist to be launched. ET-1, the most
potent endogenous vasoconstrictor known, has been demonstrated to play a major role in
the functional and structural changes observed in pulmonary hypertension. Bosentan is a
mixed ETA and ETB receptor antagonist that inhibits the pulmonary arterial vasoconstricting
effect of ET-1 predominantly mediated via ETA receptors on smooth muscle cells. In a
hypoxia-induced model of pulmonary hypertension in rat, it reduced the development of
pulmonary hypertension as well as right ventricular hypertrophy and prevented pulmonary
arterial remodeling. In clinical trials, patients treated with bosentan showed a 20% increase
in exercise capacity compared to placebo as measured by the six minute walk test.
Bosentan not only improved the distance walked by patients but also significantly
decreased mean pulmonary artery pressure, mean pulmonary vascular resistance, mean
capillary wedge pressure and mean right atrial pressure. It demonstrated a beneficial
selectivity for the pulmonary vasculature since it had no significant effect on mean aortic
blood pressure and systolic vascular resistance. The compound is hepatically metabolized
into three major metabolites by CYP3A4 and 2C9 and almost exclusively eliminated in the
bile. Although large interspecies differences in systemic plasma clearance was observed
(1.5 mL/min/kg in dogs to 72 mL/min/kg in rabbits), a satisfactory systemic clearance (2
mL/min/kg) was measured in human. The most frequent adverse effect was reversible
elevation of liver transaminases. This adverse reaction appears to be due to intracellular
accumulation of cytotoxic bile salts resulting from inhibition of the hepatocanalicular bile
salt export pump by bosentan. | | Chemical Properties | Pale Yellow to Off-White Solid | | Originator | Roche (Switzerland) | | Uses | A mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive. | | Uses | Bosentan is a mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive. | | Definition | ChEBI: 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. | | Manufacturing Process | 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-
yl]benzenesulphonamide were heated to 100°C, cooled for a further 4 hours,
poured on to ice and adjusted to pH 3 with 1 M tartaric acid. The suspension
obtained was extracted with ethyl acetate, the organic extracts were
combined, washed with water, dried with sodium sulfate and concentrated
under reduced pressure. The residue was chromatographed on silica gel with
CH2Cl2-ethyl acetate 9:1 and yielded 4-t-butyl-N-[6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]benzenesulphonamide as
a solid. Sodium salt melted at 195°-198°C.
The 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl)-pyrimidin-
4-yl]benzenesulfonamide was prepared starting from pyrimidine-2-
carboxamidine hydrochloride via rac-5-(2-methoxyphenoxy)-2-(pyrimidin-2-
yl)tetrahydropyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxyphenoxy)-
2,2'-bipyrimidine. | | Brand name | Tracleer (Actelion). | | Therapeutic Function | Endothelin receptor antagonist | | General Description | Bosentan, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tertbutyl-benzenesulfonamide (Tracleer, Bozentan), was thefirst endothelin receptor antagonist marketed in the UnitedStates. Bosentan works by competitively blocking the endothelinreceptor subtypes ETA and ETB. In binding to thereceptors, it blocks the effects of endothelin, which includeconstriction of the vascular smooth muscle, which leads tonarrowing of the blood vessels and hypertension. Althoughit is not selective for the ETA receptors, it does have a higheraffinity for that subtype over ETB. However, the clinical significanceof selectivity over preferential receptor bindinghas not been demonstrated. Bosentan is an inducer ofCYP2C9 and CYP3A4, and patients using bosentan must bemonitored for liver toxicity. | | Hazard | A reproductive hazard. | | Pharmacokinetics | Bosentan is mainly
eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites
have been identified, formed by CYP2C9 and CYP3A4. The pharmacokinetics of bosentan are
dose-proportional up to 500 mg/day (multiple doses). The pharmacokinetics of bosentan in pediatric patients with PAH
are comparable to those in healthy subjects, whereas adult patients with PAH show a twofold increase in clearance.
Severe renal impairment and mild hepatic impairment do not have a clinically relevant influence on its
pharmacokinetics. Bosentan generally should be avoided in patients with moderate or severe hepatic impairment
and/or elevated liver aminotransferases. Inhibitors of CYP3A4 increase the plasma concentration of bosentan as well
as cause an increase in the clearance of drugs metabolized by CYP3A4 and CYP2C9 because of induction of these
metabolizing enzymes. The possibility of reduced efficacy of CYP2C9 and CYP3A4 substrates coadministered with
bosentan is increased. No clinically relevant interaction was detected for P-glycoprotein. Bosentan can increase
plasma levels of ET-1. | | Clinical Use | Bosentan is an orally administered, nonselective ET-1 receptor antagonist blocking ETA and ETB receptors and is
approved for the treatment of patients with PAH. Following oral administration, bosentan attains peak plasma
concentrations in approximately 3 hours, with an absolute bioavailability of approximately 50%. Food has no clinically
relevant effect on its absorption recommended doses. Bosentan is approximately 98% bound to albumin, with a volume
of distribution of 30 L. Its terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. | | Side effects | Adverse effects include hypotension, headache, flushing, increased liver aminotransferases, leg
edema, and anemia. Bosentan may cause birth defects and, therefore, is contraindicated in pregnancy. It also can
cause liver injury. | | Drug interactions | Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antidiabetics: increased risk of hepatoxicity with
glibenclamide - avoid.
Antifungals: fluconazole, ketoconazole and
itraconazole cause large increases in concentration of
bosentan - avoid.
Antivirals: concentration of bosentan increased by
lopinavir and ritonavir - consider reducing bosentan
dose; telaprevir concentration reduced and bosentan
concentration possibly increased; avoid with
tipranavir.
Ciclosporin: When ciclosporin and bosentan are
co-administered, initial trough concentrations of
bosentan are 30 times higher than normal. At steady
state, trough levels are 3-4 times higher than normal.
Blood concentrations of ciclosporin decreased by
50% - avoid.
Cytotoxics: concentration of bosutinib possibly
reduced - avoid.
Guanfacine: concentration of guanfacine possibly
reduced - increase guanfacine dose.
Lipid lowering agents: concentration of simvastatin
reduced by 45% - monitor cholesterol levels and
adjust dose of statin.
Oestrogens, progestogens and ulipristal: may be
failure of contraception - use alternative method. | | Metabolism | Upon multiple dosing, plasma concentrations of bosentan
decrease gradually to 50%-65% of those seen after single
dose administration. This decrease is probably due to
auto-induction of metabolising liver enzymes. Steadystate conditions are reached within 3-5 days.
Bosentan is eliminated by biliary excretion following
metabolism in the liver by the cytochrome P450
isoenzymes, CYP2C9 and CYP3A4. Bosentan
forms three metabolites and only one of these is
pharmacologically active. This metabolite is mainly
excreted unchanged via the bile. In adult patients, the
exposure to the active metabolite is greater than in healthy
subjects. In patients with evidence of the presence of
cholestasis, the exposure to the active metabolite may be
increased. | | storage | Store at +4°C |
| | Bosentan Preparation Products And Raw materials |
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