Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 16, Issue 5, Pages 2473-2488Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2007.11.060
Keywords
agonist; inverse agonist; beta(3)-adrenoceptor; (alpha S : beta S)- and (alpha S : beta R)-2-{4-[2-(2-hydroxy-2 phenylethylamino)ethyl]phenoxy}propanoic acid; obesity; type 2 diabetes; heart failure; cachexia; metabolic syndrome; overactive bladder; preterm labour; anxiety and depressive disorders; DELFIA
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Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alpha R)- and (alpha S)2-14-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy)-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alpha R, beta S)- and (alpha R, beta R)- 2- 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxylpropanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alpha S, beta S)- and (alpha S, beta R)-2-14-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands. (C) 2007 Elsevier Ltd. All rights reserved.
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