Discovery of potent and orally bioavailable heterocycle-based β3-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 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 2 mg/kg.

Graphical abstractA 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. Compound 17 showed excellent agonist potency at the β3-AR, and a favorable pharmacokinetic profile in vivo. This compound increased rat oxygen consumption after oral administration, with an ED20% of 2 mg/kg.Figure optionsDownload full-size imageDownload as PowerPoint slide