Endothelin-1 receptors

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. 

The endothelin receptor subtypes show differences in their signal transduction, ligand binding and tissue distribution. The ETA receptor is isopeptide-selective and binds ET-1 and ET-2 with the same and ET-3 with 70-100-fold lower affinity. The ETB receptor binds all three isoforms with the same affinity. 

Sites of endothelin-receptor expression. ETA receptors are expressed in the smooth muscle cells of the vascular medial layer and the airways, in cardiac myocytes, lung parenchyma, bronchiolar epithelial cells and prostate epithelial cells. ETB receptors are expressed in endothelial cells, in bronchiolar smooth muscle cells, vascular smooth muscle cells of certain vessels (e.g. saphenous vein, internal mammary artety), in the renal proximal and distal tubule, the renal collecting duct and in the cells of the atrioventricular conducting system. 

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. 

Caligiuri G, Levy B, Pemow J, Thoren P, Hansson GK. Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. Proc Natl Acad Sci U S A 1999 96(12) 6920-6924. 

Roos, M., Soskic, V., Poznanovic, S., and Godovac-Zimmermaim, J. (1998). Post-translational modifications of endothelin receptor B from bovine lungs analyzed by mass spectrometry. J. Biol. Chem. 273, 924-931. 

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... 

Attie, T, Till, M., Pelet, A., et al. (1995) Mutation of the endothelin-receptor-B gene in Waardenburg-Hirschsprung-disease. Hum. Mol. Genet. 4, 2407-2409. 

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. 

R.A.F. Discovery ofTBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist./. Med. Chem. 1997, 40, 1690-1697. 

B., Okun, I., and Castillo, R.S. Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-A antagonists. 

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. 

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