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

• Published in: Bioorganic & medicinal chemistry 2001-08, Vol.9 (8), p.2045-2059
• Main Authors: Hu, B, Ellingboe, J, Han, S, Largis, E, Lim, K, Malamas, M, Mulvey, R, Niu, C, Oliphant, A, Pelletier, J, Singanallore, T, Sum, F W, Tillett, J, Wong, V
• Format: Article
• Language: English
• Subjects: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists - chemical synthesis; Adrenergic beta-Agonists - chemistry; Adrenergic beta-Agonists - pharmacology; Animals; CHO Cells; Cricetinae; Humans; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0968-0896
• DOI: 10.1016/S0968-0896(01)00114-6

A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human beta(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 beta(3) receptor. Modification of the right-hand side of the compounds by incorporation of a free 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-piperidin-1-yl-phenylamine further increased the beta(3) potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full beta(3) agonist (EC(50)=0.004 microM, IA=1.0) with > 500-fold selectivity over beta(1)- and beta(2)-ARs.