Human beta3-adrenergic receptor agonists containing 1,2,3-triazole-substituted benzenesulfonamides.
Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.
Brockunier
L L
LL
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linda_brockunier@merck.com
Parmee
E R
ER
Ok
H O
HO
Candelore
M R
MR
Cascieri
M A
MA
Colwell
L F
LF
Deng
L
L
Feeney
W P
WP
Forrest
M J
MJ
Hom
G J
GJ
MacIntyre
D E
DE
Tota
L
L
Wyvratt
M J
MJ
Fisher
M H
MH
Weber
A E
AE
D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007263:Infusions, Parenteral; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects; D008253:Macaca mulatta; D011485:Protein Binding; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D013610:Tachycardia / Q000139:chemically induced; D014230:Triazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D000096926:Benzenesulfonamides
D058667:Adrenergic beta-3 Receptor Agonists; D000242:Cyclic AMP; D007545:Isoproterenol; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D014230:Triazoles; D000096926:Benzenesulfonamides