Endothelin receptor antagonists bosentan

A product ion scan can obtain stmctural information of a given precursor ion while a precursor ion scan is more suited to find stmctural homologues in a complex mixture. Bosentan (Mr = 551, Fig. 1.19) has two metabolites corresponding to the tert-butyl hydroxylation product (Mr = 567) and the dealkylation of the me-thoxy group to form the phenol (Mr = 537). Bosentan (Tracker, Actelion Phrama-ceuticals) is an oral duel endothelin receptor antagonist approved for the use in arterial hypertension [56]. Selection of the fragment at m/z 280 can fish out precursor ions corresponding only to bosentan and these two metabolites (Fig. 1.19C). A similar result is obtained with the constant-neutral loss scan mode (Fig. 1.19D) which is based on neutral loss of 44 units. 

J. Teerlink, B.M. Loeffler, P. Hess, J.P. Maire, M. Clozel, J.P. Clozel, Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan). Circulation 90 (1994) 2510-2518. 

Bosentan is a nonselective receptor blocker. It is active orally, and blocks both the initial transient depressor (ETB) and the prolonged pressor ( ) responses to intravenous endothelin. Many orally active endothelin receptor antagonists with increased selectivity have been developed and are available for research use. Examples include the selective antagonists sitaxsentan and ambrisentan. 

Concomitant treatment with simvastatin and bosentan (the first orally active endothelin receptor antagonist) reduces exposure to simvastatin by about 40%, suggesting that in vivo bosentan is a mild inducer of CYP3A4 (38). 

Dingemanse J. Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Chn Pharmacokinet 2003 42 293-301. 

Treatment still remains difficult, because few clinical studies are available. High doses of calcium antagonists are recommended, but their frequent side effects have to be taken into account, particularly with a cardiac output of <2 1/min. (146) In severe cases, pulmonary pressure reduction by permanent infusion of epoprostenol over several weeks or long-term administration of oxygen may be helpful. Good experience has been made with the endothelin-receptor antagonist bosentan (2 x 125 mg/day). (36) (s. p. 338 )... 

Channick, R.N., Simonnean, G., Sitbon, O., Robbins, I.M., Frost, A., Tapson, V.F., Badesch, DJI., Roux, S., Rainisio, M., Bodin, F., Rubin, L.X Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension a randomized placebo-con-trolled study. Lancet 2001 358 1119-1123... 

The major safety issue that has emerged with bosentan, the endothelin receptor antagonist that has been most extensively studied in man, has been dose-dependent reversible impairment of hepatic function (3% with... 

Badesch DB, Bodin F, Channick RN, Frost A, Rainisio M, Robbins IM, Roux S, Rubin LJ, Simonneau G, Sitbon O, Tapson VF. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension. Curr Ther Res Clin Exp 2002 63 227M6. 

Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators. N Engl J Med 1998 338(12) 784-90. 

Neidhart, W., Breu, V., Bur, D., Burri, K., Clozel, M., Hirth, G., Mueller, M., Wessel, H. R, Ramuz, H. The discovery of nonpeptide endothelin receptor antagonists. Progression towards bosentan. Chimia 1996, 50, 519-524. 

Ahmadi-Simab K, Lamprecht P, Hellmisch B, Gross WL. Treatment of pulmonary arterial hypertension (PAH) with oral endothelin-receptor antagonist bosentan in systemic sclerosis BREATHE-1 trial and clinical experience. Z Rheumatol 2004 63(6) 495-7. [Article in German]... 

The plasma levels of the dual endothelin receptor antagonist bosentan decrease with multiple dosing [67] as a result of PXR-mediated autoinduction of CYP3A4 [68],... 

Bosentan is an endothelin receptor antagonist. It antagonized endothelin (ET) receptor by binding to ET and ETg receptors in the endothelium and vascular smooth muscle. Bosentan is indicated in treatment of pulmonary arterial hypertension in patients with WHO class III and IV symptoms, to improve exercise ability, and decrease the rate of clinical worsening. 

Dingemanse J, Bodin F, Weidekamm E, Kutz K, van Giersbergen P. Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol (2002) 42, 283-9. 

Liver The endothelin receptor antagonists have been associated with impaired liver function and raised aminotransferases in trials and practice. In two cases concomitant administration of bosentan and clarithromycin in systemic sclerosis led to liver dysfunction [82" ]. 

Liver The availability of ambrisentan in patients with pulmonary artery hypertension who have previously discontinued other endothelin receptor antagonists because of liver function abnormalities provides an important option for patients who have had adverse reactions to bosentan or sitaxsentan [76 ]. Ambrisentan is a... 

The use of endothelin receptor antagonists for pulmonary hypertension has been examined in 14 high-risk adults with sickle cell disease [81 ]. Most were taking bosentan and three were taking ambrisentan. There were similar adverse effects as in previous studies, including rises in serum alanine aminotransferase n = 2), peripheral edema (4), rash (1), headache (3), and reduced hemoglobin (2), none of which required drug withdrawal. 

Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension a randomised placebo-controlled study. Lancet 2001 358 1119-1123. 

Chen S-J, Chen Y-F, Meng QC, Durand J, Dicarlo VS, Oparil S. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995 79(6) 2122-2131. 

ETA-selective antagonists included a more selective (>25 000-fold) p)rrrolidine carboxylic acid derivatives A-216546 (121). A-216546 was orally available in rat, dog and monkey and blocked endothelin-1-induced presser response in conscious rats. Replacement of the dialkylacetamide side chain in 121 resulted in a complete reversal of receptor selectivity, preferring ETb over ET. Compound 122 (A-308165) demonstrated over 27 000-fold selectivity favouring the ETb receptor. So far one of the endothelin ETA-receptor antagonists bosentan (123) has reached the market for the treatment of pulmonary h)rpertension. Several other compounds have either failed in the clinic or are in various stages of development (e.g. sitaxsentan (124) and 125). ... 

Bosentan is an endothehn-A and endothehn-B receptor antagonist. It is effective in pulmonary arterial hjrpertension (1,2) and has been marketed for this indication. The studies showed an improvement in exercise capacity and dyspnea and an increased time to clinical worsening. Efficacy in pulmonary hjrpertension has also been reported in an open study with a selective endothelin-A receptor antagonist (3). 

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