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.

中文翻译：

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(E)-3-(3-((2-Cyano-4'-二甲基氨基联苯-4-基甲基)环己烷羰基氨基)-5-氟苯基)丙烯酸甲酯的发现，一种肠特异性 FXR 部分激动剂，用于治疗非酒精性脂肪性肝炎

合成并评估了一系列 fexaramine 类似物以开发肠选择性/特异性 FXR 部分激动剂。在联苯环的 C-2 处引入 CN 取代基，在苯胺环的 C-5 处引入氟，显着增加了 FXR 激动活性。在 FXR 激动剂测定中，相对于 GW4064，图27c显示出 53 ± 3% 的最大功效。大鼠口服给药后，大量27c在肠道内被吸收，然后被血清酯酶迅速代谢为无活性的羧酸44 。在 CDAHFD 喂养的小鼠中，口服27c强烈诱导多个肠道 FXR 靶基因 FGF15、SHP、IBABP 和 OST-α，但未能激活肝脏中的 SHP。27c显着降低了肝纤维化面积、肝纤维化标志物和AST的血清水平。fexaramine 的合理优化导致了肠道特异性 FXR 部分激动剂27c的鉴定。