Cardiovascular disease endothelin antagonists

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. 

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. 

There is increasing evidence that endothelins participate in a variety of cardiovascular diseases, including hypertension, cardiac hypertrophy, heart failure, atherosclerosis, coronary artery disease, and myocardial infarction. Endothelins have also been implicated in pulmonary diseases, including asthma and pulmonary hypertension, as well as in several renal diseases. This evidence includes findings of increased endothelin levels in the blood, increased expression of endothelin mRNA in endothelial or vascular smooth muscle cells, and the responses to administration of endothelin antagonists. 

The search for endothelin antagonists as potential compounds for treating cardiovascular disease was noted in Chapter 5 (see atrasentan). A composed with a considerably simpler structure incorporates a pyrimidine ring in the side chain. Condensation of benzophenone (94) with ethyl chloro-acetate and sodium methoxide initially proceeds to addition of the enolate from the acetate to the benzophenone carbonyl. The aUcoxide anion on the first-formed quaternary carbon then displaces chlorine on the acetate to leave behind the oxirane in the observed product (95). Methanolysis of the epoxide in the product in the presence of boron triflor-ide leads to the ether-alcohol (96). Reaction of this with the pyrimidine (97) in the presence of base leads to displacement of the methanesulfonyl group by the aUcoxide from 96. Saponification of the ester group in that product gives the corresponding acid, ambrisentan (98). " ... 

Endothelin and its related peptides play an important role in the biology of vascular smooth muscle. Antagonists of the endothelin receptor would be of great interest in the treatment of cardiovascular and pulmonary disease. One such compound is SB-209670 101 and could be prepared from alcohol 100.28 This alcohol could be accessed via the CBS reduction of indenone 99 in excellent yield and excellent optical purity. 

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