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 β3 adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human β3 agonists with excellent selectivity against other human β receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F3C-C6H4) is a potent full β3 agonist (EC50 = 3.6 nM, 94% activation) with >600-fold selectivity over the human β1 and β2 receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.