title: Discovery of potent and orally bioavailable heterocycle-based beta3-adrenergic receptor agonists, potential therapeutics for the treatment of obesity.
abstract: 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.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. jennifer.lafontaine@pfizer.com
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lafontaine
authors.forename: Robert F
authors.initials: RF
authors.lastname: Day
authors.forename: Joe
authors.initials: J
authors.lastname: Dibrino
authors.forename: John R
authors.initials: JR
authors.lastname: Hadcock
authors.forename: Diane M
authors.initials: DM
authors.lastname: Hargrove
authors.forename: Michael
authors.initials: M
authors.lastname: Linhares
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Martin
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Nardone
authors.forename: David A
authors.initials: DA
authors.lastname: Tess
authors.forename: Paul
authors.initials: P
authors.lastname: Dasilva-Jardine
mesh_terms: 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
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists