Non-alcoholic fatty liver disease (NAFLD), attributed to excessive fat accumulation in the liver, is reportedly prevalent worldwide. NAFLD is one of the leading causes of chronic liver disease, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatic cellular carcinoma (HCC). The peripheral roles of serotonin (5-hydroxytryptamine, 5HT) were found to regulate hepatic lipid metabolism. Among serotonin receptor subtypes, 5HT_2A receptor is known to regulate hepatic lipid metabolism. Hepatic lipid accumulation and hepatic triglyceride (TG) were reduced in liver-specific 5HT_2A receptor knockout (5HT_2A receptor LKO) mice upon high-fat diet (HFD) feeding. In the present study, we explored a series of new peripherally acting 5HT_2A receptor antagonists. Compound 14a displayed good in vitro activity, with an IC₅₀ value of 0.17 nM. Compound 14a exhibited good microsomal stability, no significant CYP and hERG inhibition, and 5HT receptor subtype selectivity. The brain-to-plasma ratio of 14a was below the lower limit of quantification, indicating limited blood-brain barrier (BBB) penetration. HFD-fed 14a treated mice showed decreased liver steatosis and lobular inflammation. These results demonstrate the potential of newly synthesized peripheral 5HT_2A receptor antagonists for treating NAFLD.

据报道，非酒精性脂肪性肝病 (NAFLD) 归因于肝脏中过多的脂肪堆积，在世界范围内普遍存在。NAFLD 是慢性肝病的主要原因之一，包括非酒精性脂肪性肝炎 (NASH)、肝硬化和肝细胞癌 (HCC)。发现血清素（5-羟色胺，5HT）的外周作用可调节肝脏脂质代谢。在血清素受体亚型中，已知5HT _{2A受体调节肝脏脂质代谢。}高脂饮食 (HFD) 喂养后肝脏特异性5HT _2A受体敲除 ( 5HT _{2A受体 LKO) 小鼠的肝脏脂质积累和肝脏甘油三酯 (TG) 减少。}在本研究中，我们探索了一系列新的外周作用 5HT_2A受体拮抗剂。化合物14a表现出良好的体外活性，IC ₅₀值为0.17 nM。化合物14a表现出良好的微粒体稳定性，没有显着的 CYP 和 hERG 抑制，以及 5HT 受体亚型选择性。14a的脑血浆比低于量化下限，表明血脑屏障 (BBB) 渗透有限。喂食 HFD 的14a处理的小鼠表现出肝脏脂肪变性和小叶炎症减少。这些结果证明了新合成的外周 5HT _2A受体拮抗剂治疗 NAFLD 的潜力。