Discovery of benzamides as potent human β3 adrenergic receptor agonists

The paper will describe the synthesis and SAR studies that led to the discovery of benzamide ( reverse amide) as potent and selective human beta(3)-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human beta(3)-adrenergic potency and good selectivity over the beta(1) and beta(2) receptors. In addition to human beta(1), beta(2), beta(3) and hERG data, PK of selected compounds will be described. (C) 2015 Elsevier Ltd. All rights reserved.