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.

β-肾上腺素能受体（β-ARs）广泛分布在各种组织中，并调节一系列重要的生理功能和疾病状态，包括癌症。首先，β ₃肾上腺素能受体（β ₃ -AR）发挥了在脂肪组织中脂肪分解调节和产热一个显著的作用。在这项研究中，我们设计并合成了一系列新的L-748337衍生物作为选择性人β ₃ -AR拮抗剂。在所有被测试的L-748337类似物，化合物23d中被发现显示23倍更有效的β ₃ -AR拮抗剂活性（EC ₅₀  = 0.5117 nM）的比L-748337（EC ₅₀  = 11.91 nM）的。体内化合物23d 在C26肿瘤恶病质动物模型中可以减轻体重并抑制肿瘤生长。