Novel (4-Piperidin-1-yl)-phenyl Sulfonamides as Potent and Selective Human β3 Agonists

Abstract A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human β 3 -adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the β 3 receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human β 3 agonists with low affinities for β 1 - and β 2 -ARs. N -Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the β 3 potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full β 3 agonist (EC 50 =0.004 μM, IA=1.0) with >500-fold selectivity over β 1 - and β 2 -ARs.