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
Chemical Sciences, Wyeth-Ayerst Research, Pearl River, NY 10965, USA.
Bioorg Med Chem. 2001 Aug;9(8):2045-59. 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.
制备了一系列新型的(4-哌啶-1-基)-苯磺酰胺，并评估了它们对人β(3)-肾上腺素能受体(AR)的生物活性。在化合物左侧，将儿茶酚部分的3,4-二羟基用4-羟基-3-甲基磺酰胺取代，产生了许多β(3)受体的强效完全激动剂。通过引入游离羧酸对化合物右侧进行修饰，得到了一些对β(1)-和β(2)-ARs亲和力低的强效人β(3)激动剂。4-哌啶-1-基-苯胺上的N-烷基取代进一步提高了β(3)效力，同时保持了选择性。例如，磺酰胺48是一种强效的完全β(3)激动剂(EC(50)=0.004 microM，IA=1.0)，对β(1)-和β(2)-ARs的选择性大于500倍。
