Discovery of potent and orally bioavailable heterocycle-based beta3-adrenergic receptor agonists, potential therapeutics for the treatment of obesity.
A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED(20%) of 2mg/kg.
Lafontaine
Jennifer A
JA
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. jennifer.lafontaine@pfizer.com
Day
Robert F
RF
Dibrino
Joe
J
Hadcock
John R
JR
Hargrove
Diane M
DM
Linhares
Michael
M
Martin
Kelly A
KA
Maurer
Tristan S
TS
Nardone
Nancy A
NA
Tess
David A
DA
Dasilva-Jardine
Paul
P
D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001682:Biological Availability; D009765:Obesity / Q000188:drug therapy*; D051381:Rats
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists