Discovery of a potent, orally bioavailable beta(3) adrenergic receptor agonist, (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide

As part of our investigation into the development of orally bioavailable be ta (3) adrenergic receptor agonists, we have identified a series of pyridyl ethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta (3) agonists with excellent selec tivity against other human beta receptor subtypes. Several of these compoun ds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F3C-C6H4) is a potent full beta (3) agonist (EC50 = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta (1) and beta (2) receptors, which also displays good oral bioavailabil ity in several mammalian species, as well as an extended duration of action .