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Design and synthesis of aryloxypropanolamine as β 3 -adrenergic receptor antagonist in cancer and lipolysis.
European Journal of Medicinal Chemistry 2018 April 26
β-adrenergic receptors (β-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, β3 -adrenergic receptor (β3 -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 β3 -AR antagonists. Among all the tested L-748,337 analogs, compound 23d was found to display 23-fold more potent β3 -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.
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