Novel substituted 4-aminomethylpiperidines as potent and selective human beta3-agonists. Part 1: aryloxypropanolaminomethylpiperidines.
The synthesis and SAR of a series of human beta3 adrenoreceptor agonists based on a template derived from a common pharmacophore coupled with 4-aminomethylpiperidine is described. Potent and selective agents were identified such as 26 that was in vitro active in CHO cells expressing human beta3-AR (EC50=49 nM, IA=1.1), and in vivo active in a transgenic mouse model.
Steffan
Robert J
RJ
Chemical Sciences, Wyeth Research, 500 Arcola Rd, Collegeville, PA 19426, USA. steffar@wyeth.com
Ashwell
Mark A
MA
Solvibile
William R
WR
Matelan
Edward
E
Largis
Elwood
E
Han
Stella
S
Tillet
Jeffery
J
Mulvey
Ruth
R
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics; D013329:Structure-Activity Relationship
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D007202:Indicators and Reagents; D010880:Piperidines; D022702:Receptors, Adrenergic, beta-3