Discovery of (<i>E</i>)‑3-(3-((2-Cyano-4′-dimethylaminobiphenyl-4-ylmethyl)cyclohexanecarbonylamino)-5-fluorophenyl)acrylic Acid Methyl Ester, an Intestine-Specific, FXR Partial Agonist for the Treatment of Nonalcoholic Steatohepatitis

A series of fexaramine analogs were synthesized and evaluated to develop an intestine-selective/specific FXR partial agonist. Introduction of both a CN substituent at the C-2 in the biphenyl ring and a fluorine at the C-5 in the aniline ring in fexaramine markedly increased FXR agonistic activity. 27c showed 53 ± 3% maximum efficacy relative to GW4064 in an FXR agonist assay. A substantial amount of 27c was absorbed in the intestine after oral administration in rats, and then it was rapidly metabolized to inactive carboxylic acid 44 by serum esterases. In CDAHFD-fed mice, oral administration of 27c strongly induced multiple intestinal FXR target genes, FGF15, SHP, IBABP, and OST-α, but failed to activate SHP in the liver. 27c significantly reduced the liver fibrogenesis area, hepatic fibrosis markers, and serum level of AST. Rational optimization of fexaramine has led to the identification of an intestine-specific FXR partial agonist 27c.本研究合成并评估了一系列非沙胺（fexaramine）类似物，旨在开发肠道选择性/特异性法尼醇X受体（Farnesoid X Receptor, FXR）部分激动剂。在非沙胺的联苯环C-2位引入氰基取代基、苯胺环C-5位引入氟原子，可显著提升其FXR激动活性。在FXR激动剂活性检测实验中，化合物27c的最大效能为GW4064的53±3%。大鼠口服给予27c后，该化合物可在肠道被大量吸收，随后迅速被血清酯酶代谢为无活性的羧酸类产物44。在饲喂胆碱缺乏高脂饮食（CDAHFD）的小鼠中，口服给予27c可强力诱导肠道内多种FXR靶基因的表达，包括FGF15、SHP、IBABP及OST-α，但无法激活肝脏中的SHP基因。27c可显著降低肝脏纤维化区域面积、肝纤维化标志物水平及血清中天冬氨酸氨基转移酶（Aspartate Aminotransferase, AST）的含量。通过对非沙胺的合理优化，最终得到了肠道特异性FXR部分激动剂27c。