Stereospecific synthesis and bio-activity of novel β₃-adrenoceptor agonists and inverse agonists

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• 作者：Maria Grazia Perrone ; Ernesto Sant ; rea ; Laura Bleve ; Paola Vitale ; Nicola Antonio Colabufo ; Ralf Jockers ; Ferdin ; o Maria Milazzo ; Anna Floriana Sciarroni ; Antonio Scilimati
• 关键词：Agonist ; Inverse agonist ; none ; color ; black" href="/science?_ob=MathURL&_method=retrieve&_udi=B6TF8-4R7J81B-C&_mathId=mml62&_user=1067359&_cdi=5220&_rdoc=30&_acct=C000050221&_version=1&_userid=10&md5=4b6f73217
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 March 2008
• 卷：16
• 期：5
• 页码：2473-2488
• 文件大小：314 K

摘要

Since it is widely distributed into the body, 050221&_version=1&_userid=10&md5=1ba55d23f4601cfae39222afc7698ef7" title="Click to view the MathML source" alt="Click to view the MathML source">β₃-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 050221&_version=1&_userid=10&md5=fd45cc38f1fe6f1efa2be36de42df51f" title="Click to view the MathML source" alt="Click to view the MathML source">β₃-adrenoceptor and their affinity for 050221&_version=1&_userid=10&md5=9137adb698faa64ab2ccfd911e23737f" title="Click to view the MathML source" alt="Click to view the MathML source">β₁- and 050221&_version=1&_userid=10&md5=82678a5780f45856978942f470bfc9ff" title="Click to view the MathML source" alt="Click to view the MathML source">β₂-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, 050221&_version=1&_userid=10&md5=9e5eac563c128166fb0f8677831e96a1" title="Click to view the MathML source" alt="Click to view the MathML source">-racemic, (050221&_version=1&_userid=10&md5=e7ac0dac512a5f7daacde75996563486" title="Click to view the MathML source" alt="Click to view the MathML source">R)- and (050221&_version=1&_userid=10&md5=6463a02db395abd39c7b26e0c9f0227f" title="Click to view the MathML source" alt="Click to view the MathML source">S)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (050221&_version=1&_userid=10&md5=a76cc949b8451f3ab8a76e2030b3939d" title="Click to view the MathML source" alt="Click to view the MathML source">-rac, 050221&_version=1&_userid=10&md5=1a29a6d33e227dde72803b54c0db0eeb" title="Click to view the MathML source" alt="Click to view the MathML source">β-rac)-, (050221&_version=1&_userid=10&md5=b5642fdc8b800eba49cdf0250ec60a31" title="Click to view the MathML source" alt="Click to view the MathML source">R, 050221&_version=1&_userid=10&md5=00f87a3524599d5128af011ceedd8019" title="Click to view the MathML source" alt="Click to view the MathML source">βS)- and (050221&_version=1&_userid=10&md5=1b01d1107863ce1f0a04bb2768c2fd21" title="Click to view the MathML source" alt="Click to view the MathML source">R, 050221&_version=1&_userid=10&md5=30de39812b28bf8d85b246f1b58b4057" title="Click to view the MathML source" alt="Click to view the MathML source">βR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with 050221&_version=1&_userid=10&md5=2440707273bcea0137f59495c158ad2f" title="Click to view the MathML source" alt="Click to view the MathML source">β₃-adrenoceptor agonistic activity. Whereas, (050221&_version=1&_userid=10&md5=bced8949ff402a33d9a46ff942bdd590" title="Click to view the MathML source" alt="Click to view the MathML source">S, 050221&_version=1&_userid=10&md5=e0e079e3d31dd6720d7b41e35bb5e458" title="Click to view the MathML source" alt="Click to view the MathML source">βS)- and (050221&_version=1&_userid=10&md5=e9651da97a95957a14e3725f5bde1ad5" title="Click to view the MathML source" alt="Click to view the MathML source">S, 050221&_version=1&_userid=10&md5=03f7aeeba31a4990fbfe457a772e23f9" title="Click to view the MathML source" alt="Click to view the MathML source">βR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as 050221&_version=1&_userid=10&md5=f9f911f1e4eaffbbc38d5060272925f5" title="Click to view the MathML source" alt="Click to view the MathML source">β₃-adrenoceptor inverse agonists. Such compounds showed no affinity for 050221&_version=1&_userid=10&md5=8795b829479ed4f5d451cf25b049f937" title="Click to view the MathML source" alt="Click to view the MathML source">β₁- and 050221&_version=1&_userid=10&md5=c10fa90ab8b9ec0eed94023b222fce7b" title="Click to view the MathML source" alt="Click to view the MathML source">β₂-adrenergic receptor, respectively. Thus, resulting highly selective 050221&_version=1&_userid=10&md5=23f79d3ddd73f06c4080bff7459e9cbe" title="Click to view the MathML source" alt="Click to view the MathML source">β₃-adrenoceptor ligands.