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.
Shim S, Krishnaiah M, Sankham MR, Kim I, Lee Y, Shin I, Oh AR, Lee HJ, Vu TNL, Park J, Choi S, Park S, Kwon Y, Fang S, Kim DK.
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. <b>27c</b> showed 53 ± 3% maximum efficacy relative to GW4064 in an FXR agonist assay. A substantial amount of <b>27c</b> was absorbed in the intestine after oral administration in rats, and then it was rapidly metabolized to inactive carboxylic acid <b>44</b> by serum esterases. In CDAHFD-fed mice, oral administration of <b>27c</b> strongly induced multiple intestinal FXR target genes, FGF15, SHP, IBABP, and OST-α, but failed to activate SHP in the liver. <b>27c</b> 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 <b>27c</b>.