Endothelin receptor antagonist

Ro 46-2005 (140) and SB 209670 (141) are the first synthetic orally active endothelin receptor antagonists. The ET receptor is a third ET receptor. 

As endothelins mediate potent vasoconstrictor effects, ECE inhibitors and endothelin receptor antagonists were developed for the treatment of cardiovascular diseases, such as acute and chronic heart failure, pulmonary hypertension and subarachnoid haemorrhage. As ETa recqrtors have potent mitogenic responses and may promote progression of ovarian and prostate cancer and bone metastases ETA receptors are also considered as a potential targets for anti-tumour activity. 

Endothelins. Table 3 Summary of clinical trials with endothelin receptor antagonists or ECE-inhibitors... 

Stenberg, P., Luthman, K., Ellens, H., Lee, C. P., Smith, Ph. L, Lago, A., Elliott, J. D. Artursson, P. Prediction of the intestinal absorption of endothelin receptor antagonists using three theoretical methods of increasing complexity. Pharm. Res. 1999, 16, 1520-1526. 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

P. Artursson. Prediction of the intestinal absorption of endothelin receptor antagonists using three theoretical methods of increasing complexity, Pharm. Res. 1999, 36, 1520-1526... 

Palladium catalyzed cross coupling of arylboronic acid to nonracemic trifluoromethylsulfonyl and fluorosulfonyl enol ethers is one of the key steps in the synthesis two endothelin receptor antagonists, SB 209670 and SB 217242, which have been clinically evaluated for several illnesses including hypertension, ischemia, stroke and others [37] (Scheme 6.14). 

A 3D-QSAR analysis of in vitro binding affinity and selectivity of 3-izoxazolyl-sulfonylaminothiophenes as endothelin receptor antagonists. Quant. Struct.-Act. Relot. 1999, 18, 124-133. 

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. 

Ertl G. Endothelin receptor antagonists in heart failure. Drugs 2004 64 1029-40. 

Endothelins are a family of vasoactive peptides secreted by endothelial cells. The three major endothelin peptides are all composed of 21 amino acids. Endothelins are the most potent vasoconstrictors known. Contraction of vascular smooth muscle in response to endothelin is associated with an increase in intracellular calcium. Increases in endothelin levels have been reported in patients with vasospastic, hypoxic, and ischemic diseases. The two identified isoforms of endothelin receptors have differing affinity for the three endothelin peptides. Selective and nonselective endothelin receptor antagonists are in development for potential use in the treatment of hypertension and other disorders associated with increased vascular resistance. 

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. 

B. Nguyen, T.J. Opgenorth, Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETa receptor selectivity, Bioorg. Med. Chem. 

E. H. Ohistein, 1,3-Diarylindan-2-carboxylic acids potent and selective non-peptide endothelin receptor antagonists, J. Med. Chem. 37 (1994) 1553-1557. 

Endothelin receptor antagonists 134 and 135 were prepared from the triflated oxicam derivative 136 (Scheme 18) <1998BMC1447>. Addition of aryl thiol 137 to the position gave product 134. Palladium-catalyzed Suzuki coupling of aryl boronic acid 138 and aryl triflate 136 affords the sulfonamide product 135. 

Parke-Davis workers have performed SAR studies on endothelin receptor antagonists derived from a dimethoxy-substituted oxicam in the search of treatments for hypertension, congestive heart failure, renal failure, pulmonary hypertension, ischemia, and cerebral vasospasm <1998BMC1447>. Compound 295 displayed a 40-fold selectivity for endothelin receptor antagonist A (ETa) over endothelin receptor antagonist B (ETb) (Figure 26). 

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. 

The formation of endothelins can be blocked by inhibiting endothelin-converting enzyme with phosphoramidon. Phosphoramidon is not specific for endothelin-converting enzyme, but several more selective inhibitors are now available for research. Although the therapeutic potential of these drugs appeared similar to that of the endothelin receptor antagonists (see below), their use has been eclipsed by endothelin antagonists. 

Systemic administration of endothelin receptor antagonists or endothelin-converting enzyme inhibitors causes vasodilation and decreases arterial pressure in humans and experimental animals. Intra-arterial administration of the drugs also causes slow-onset forearm vasodilation in humans. These observations provide evidence that the endothelin system participates in the regulation of vascular tone, even under resting conditions. The activity of the system is higher in males than in females. It increases with age, an effect that can be counteracted by regular aerobic exercise. 

Dupuis J, Hoeper MM Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008 31 407. [PMID 18238950]... 

Iodinated radiographic contrast media can cause acute renal insufficiency, perhaps as a result of reduced renal blood flow, an intrarenal osmotic effect, or direct tubular toxicity (58). Diuretics, calcium channel blockers, adenosine receptor antagonists, acetylcysteine, low-dose dopamine, the dopamine Di receptor agonist fenoldopam, endothelin receptor antagonists, and captopril have all been used to prevent contrast nephropathy. 

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. 

Jansen, R. Knopp, M. Amberg, W. Bernard, H. Koser, S. Muller, S. Munster, I. Pfeiffer, T. Riechers, H. Structural similarity and its surprises endothelin receptor antagonists process research and development report. 

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