title: Novel (4-piperidin-1-yl)-phenyl sulfonamides as potent and selective human beta(3) agonists.
abstract: 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.
authors.affiliation: Chemical Sciences, Wyeth-Ayerst Research, Pearl River, NY 10965, USA. hub@war.wyeth.com
authors.forename: B
authors.initials: B
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: Ellingboe
authors.forename: S
authors.initials: S
authors.lastname: Han
authors.forename: E
authors.initials: E
authors.lastname: Largis
authors.forename: K
authors.initials: K
authors.lastname: Lim
authors.forename: M
authors.initials: M
authors.lastname: Malamas
authors.forename: R
authors.initials: R
authors.lastname: Mulvey
authors.forename: C
authors.initials: C
authors.lastname: Niu
authors.forename: A
authors.initials: A
authors.lastname: Oliphant
authors.forename: J
authors.initials: J
authors.lastname: Pelletier
authors.forename: T
authors.initials: T
authors.lastname: Singanallore
authors.forename: F W
authors.initials: FW
authors.lastname: Sum
authors.forename: J
authors.initials: J
authors.lastname: Tillett
authors.forename: V
authors.initials: V
authors.lastname: Wong
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D010880:Piperidines; D013449:Sulfonamides