Design and synthesis of aryloxypropanolamine as β3-adrenergic receptor antagonist in cancer and lipolysis

beta-adrenergic receptors (beta-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, beta(3)-adrenergic receptor (beta(3)-AR) plays a significant role in regulating lipolysis and thermogenesis in adipose tissue. In this study, we designed and synthesized a series of novel L-748,337 derivatives as selective human beta(3)-AR antagonists. Among all the tested L-748,337 analogs, compound 23d was found to display 23-fold more potent beta(3)-AR antagonist activity (EC50 = 0.5117 nM) than L-748,337 (EC50 = 11.91 nM). In vivo, compound 23d could alleviate weight loss and inhibit tumor growth in C26 tumor cachexia animal model. (C) 2018 Elsevier Masson SAS. All rights reserved.