Discovery of potent and orally bioavailable heterocycle-based beta3-adrenergic receptor agonists, potential therapeutics for the treatment of obesity

  • Bioorg Med Chem Lett. 2007 Sep 15;17(18):5245-50. doi: 10.1016/j.bmcl.2007.06.072.
Jennifer A Lafontaine  1 ,  Robert F Day ,  Joe Dibrino ,  John R Hadcock ,  Diane M Hargrove ,  Michael Linhares ,  Kelly A Martin ,  Tristan S Maurer ,  Nancy A Nardone ,  David A Tess ,  Paul Dasilva-Jardine
Affiliations
  • 1. Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. [email protected]
PMID: 17632003 DOI: 10.1016/j.bmcl.2007.06.072
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.