Novel (4-piperidin-1-yl)-phenyl sulfonamides as potent and selective humanbeta(3) agonists

A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and e valuated for their biological activity on the human beta (3)-adrenergic rec eptor (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 beta (3) receptor. Mod ification of the right-hand side of the compounds by incorporation of a fre e carboxylic acid resulted in a few potent human beta (3) agonists with low affinities for beta (1)- and beta (2)-ARs. N-Alkyl substitution on the 4-p iperidin-1-yl-phenylamine further increased the beta (3) potency while main taining the selectivity. For example, sulfonamide 48 is a potent full beta (3) agonist (EC50 = 0.004 muM, IA = 1.0) with > 500-fold selectivity over b eta (1)- and beta (2)-ARs. (C) 2001 Elsevier Science Ltd. All rights reserv ed.