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

Since it is widely distributed into the body, β3β3-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 β3β3-adrenoceptor and their affinity for β1β1- and β2β2-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, αα-racemic, (ααR  )- and (ααS  )-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (αα-rac, ββ-rac)-, (ααR  , ββS  )- and (ααR  , ββR  )- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with β3β3-adrenoceptor agonistic activity. Whereas, (ααS  , ββS  )- and (ααS  , ββR  )-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as β3β3-adrenoceptor inverse agonists. Such compounds showed no affinity for β1β1- and β2β2-adrenergic receptor, respectively. Thus, resulting highly selective β3β3-adrenoceptor ligands.

Figure optionsDownload as PowerPoint slide