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.
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