Author/Authors :
Baihua Hu، نويسنده , , John Ellingboe، نويسنده , , Stella Han، نويسنده , , Elwood Largis، نويسنده , , Kitae Lim، نويسنده , , Michael Malamas، نويسنده , , Ruth Mulvey، نويسنده , , Chuansheng Niu، نويسنده , , Alexander Oliphant، نويسنده , , Jeffrey Pelletier، نويسنده , , Thiruvikraman Singanallore، نويسنده , , Fuk-Wah Sum، نويسنده , , Jeff Tillett، نويسنده , , Victoria Wong، نويسنده ,
Abstract :
A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human β3-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 β3 receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human β3 agonists with low affinities for β1- and β2-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the β3 potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full β3 agonist (EC50=0.004 μM, IA=1.0) with >500-fold selectivity over β1- and β2-ARs.
