Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since its discovery in 1988 by Yanagisawa et al., endothelin (ET), a potent vasoconstrictor, has been widely implicated in the pathophysiology of cardiovascular, cerebrovascular, and renal diseases. Many research groups have embarked on the discovery and development of ET receptor antagonists for the treatment of such diseases. While several compounds, e.g., ambrisentan 2, are in late clinical trials for various indications, one compound (bosentan, Tracleer) is being marketed to treat pulmonary arterial hypertension. Inspired by the structure of ambrisentan 2, we designed a novel class of ET receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-one scaffold. Here, we report on the preparation as well as the in vitro and in vivo structure-activity relationships of these derivatives. Potent dual ET(A)/ET(B) receptor antagonists with affinities in the low nanomolar range have been identified. In addition, several compounds efficiently reduced arterial blood pressure after oral administration to Dahl salt sensitive rats. In this animal model, the efficacy of the benzo[e][1,4]diazepin-2-one derivative rac-39au was superior to that of racemic ambrisentan, rac-2.
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PMID:Novel benzo[1,4]diazepin-2-one derivatives as endothelin receptor antagonists. 1513 56

Bosentan (Tracleer, Actelion Pharmaceuticals Ltd) is an oral dual endothelin receptor antagonist approved for use in functional class III to IV pulmonary arterial hypertension. In two placebo-controlled trials, patients receiving bosentan showed improved functional class, 6-minute walk distance and hemodynamics over a 12- to 16-week period. Follow-up data over 3 years has shown few deteriorations,with the majority of patients maintaining their response to bosentan alone. Investigations exploring the use of bosentan as an add-on agent to intravenous epoprostenol (Flolan, GlaxoSmithKline Plc) in those with the most severe disease are ongoing. Bosentan may also have antifibrotic properties and its use in pulmonary fibrosis is being explored. Ease of administration of bosentan with twice-daily oral dosing will provide many patients with pulmonary hypertension an option for treatment without the risks and discomforts of continuous intravenous medication.
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PMID:Bosentan. 1515 66

Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation.
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PMID:Endothelin receptor antagonists in pulmonary arterial hypertension. 1519 80

Bosentan, an endothelin-1 antagonist that can be administered orally, has been shown to be effective in the treatment of idiopathic pulmonary arterial hypertension and may be of benefit to patients with the Eisenmenger syndrome. Nine patients with Eisenmenger's syndrome were treated with bosentan at a dose of 125 mg twice a day. After treatment with bosentan, 6 of 9 patients (67%) had an improvement in New York Heart Assocation classification of >/=1 grades (p = 0.03). Oxygen saturation levels increased from 79 +/- 5% to 88 +/- 6%, (p = 0.03). The side effects of bosentan therapy were minor; no significant changes in liver function tests were noted. These preliminary data suggest that oral administration of bosentan therapy for Eisenmenger's syndrome results in improved oxygenation and functional status with minimal side effects.
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PMID:Initial experience with bosentan therapy in patients with the Eisenmenger syndrome. 1567 May 66

Clinical studies have shown the importance of endothelin as a pathogenic mediator in pulmonary arterial hypertension (PAH). We describe the effects of bosentan, an oral dual endothelin receptor antagonist, in patients with PAH associated with human immunodeficiency virus (HIV) infection. In this prospective study, 16 patients with PAH associated with HIV infection in stable condition received bosentan for 16 weeks. Efficacy endpoints included exercise capacity, cardiopulmonary hemodynamics, Doppler echocardiography, New York Heart Association functional class, and quality of life (SF-36 and EQ-5D). Safety was assessed by laboratory tests, vital signs, and adverse events. Improvements were observed from baseline to Week 16 in all efficacy parameters: 6-minute walk distance (+91 +/- 60 m, p < 0.001), New York Heart Association class (14 patients improved), hemodynamics (cardiac index: +0.9 +/- 0.7 L/minute/m(2), p < 0.001), Doppler echocardiographic variables, and quality of life. During the study, no patient died and none required epoprostenol treatment. Hepatic tolerability was similar to that reported in patients with PAH. Bosentan had no negative impact on control of HIV infection. Although limited by uncontrolled design, small sample size and short duration, this study suggests that bosentan may benefit patients with PAH associated with HIV infection, and that endothelin is an important pathogenic mediator in this disease.
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PMID:Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. 1531 66

Bosentan, a dual endothelin receptor blocker, has been used clinically to treat idiopathic pulmonary arterial hypertension (IPAH). However, the mechanism of its antiproliferative effect on pulmonary artery smooth muscle cells (PASMCs) remains unclear. A rise in cytoplasmic Ca2+ stimulates PASMC proliferation and the canonical transient receptor potential (TRPC) channels are an important pathway for Ca2+ entry during PASMC proliferation. Bosentan (20-50 microM) significantly inhibited endothelin-1- or platelet-derived growth factor (PDGF)-mediated PASMC growth and [3H]thymidine uptake. In PASMCs, endothelin-1 (1 microM) and PDGF (10 ng/ml) both upregulated protein expression of TRPC6, whereas bosentan markedly downregulated TRPC6 protein levels. Furthermore, TRPC6 expression in PASMCs from patients with IPAH was greater than in normal PASMCs, and the antiproliferative effect of bosentan was significantly enhanced in IPAH-PASMCs in comparison with normal PASMCs. These observations demonstrate that the antiproliferative effect of bosentan on PASMCs involves the downregulation of TRPC6 channels via a mechanism possibly independent of endothelin receptor blockade. The greater effect of bosentan on IPAH-PASMCs than on normal PASMCs suggests that increased TRPC6 expression and function may be involved in the overgrowth of PASMCs in patients with IPAH.
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PMID:Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes. 1531 71

Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125 mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30 L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3-5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal impairment (creatinine clearance 15-30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and beta-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin. In healthy subjects, bosentan doses >300 mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.
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PMID:Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. 1556 89

Bosentan is a dual endothelin receptor antagonist in development for the treatment of pulmonary arterial hypertension in Japan, whereas it is registered for this indication in Europe and the United States. The present study was conducted to compare the pharmacokinetics of bosentan in Caucasian and Japanese subjects. In a double-blind, placebo-controlled, ascending single-dose, 5-way crossover study, 10 healthy Caucasian and 10 Japanese subjects (1:1 male/female ratio) received single doses of 31.25, 62.5, 125, and 250 mg of bosentan or placebo. Pharmacokinetic profiles of bosentan and its pharmacologically active hydroxy metabolite, Ro 48-5033, were determined after each dose of bosentan. The pharmacokinetics of bosentan were similar and dose proportional in both ethnic groups. However, peak plasma concentration values of Ro 48-5033 were significantly greater in Japanese subjects (P < .05). This difference could not be explained by the lower body weight of the Japanese subjects. Females in both groups tended to have higher exposure to both bosentan and Ro 48-5033 than males. The results suggest that, based on pharmacokinetic grounds, no dose adjustment of bosentan is necessary when used to treat Japanese patients in comparison to Caucasian patients.
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PMID:Comparative investigation of the pharmacokinetics of bosentan in Caucasian and Japanese healthy subjects. 1560 4

New drugs for pulmonary arterial hypertension have shown efficacy in randomized controlled trials. Endothelin receptor antagonists (ERA) and prostanoids are most important for clinical practice. Bosentan represents the first approved orally active therapy for PAH. Besides its hepatotoxicity it is mostly well tolerated. The first approved prostanoid, epoprostenol, is currently first choice only for decompensated right heart failure in PAH. It has to be delivered continuously intravenously and is prone to complications, side effects and very high costs. Alternatively, subcutaneous treprostinil can be applied. It is less risky and expensive but may cause local pain at the infusion site. Inhaled iloprost combines the features of a prostanoid with pulmonary and intrapulmonary selectivity. Alternatively, iloprost is being used as continuous intravenous infusion. The phosphodiesterase-5 inhibitor sildenafil was effective in two randomized controlled trials but has not been approved for PAH therapy.
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PMID:[Therapy of pulmonary arterial hypertension]. 1570 89

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.
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PMID:Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship. 1585 28


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