Discovery of potent and orally bioavailable heterocycle-based β 3-adrenergic receptor agonists, potential therapeutics for the treatment of obesity

…, NA Nardone, DA Tess, P DaSilva-Jardine

Index: Lafontaine, Jennifer A.; Day, Robert F.; Dibrino, Joe; Hadcock, John R.; Hargrove, Diane M.; Linhares, Michael; Martin, Kelly A.; Maurer, Tristan S.; Nardone, Nancy A.; Tess, David A.; DaSilva-Jardine, Paul Bioorganic and Medicinal Chemistry Letters, 2007 , vol. 17, # 18 p. 5245 - 5250

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Citation Number: 18

Abstract

A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human β3-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the β3-AR, functional selectivity against β1- and β2-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED20% of 2mg/kg.