Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders

As a continuation of previous efforts
in mapping functional hot
spots on the bile acid scaffold, we here demonstrate that the introduction
of a hydroxy group at the C11β position affords high selectivity
for FXR. In particular, the synthesis and FXR/TGR5 activity of novel
bile acids bearing different hydroxylation patterns at the C ring
are reported and discussed from a structure–activity standpoint.
The results obtained led us to discover the first bile acid derivative
endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic
acid (TC-100, 7) which also shows a remarkable physicochemical
and pharmacological profile. Compound 7 combines the
excellent physicochemical properties of hydrophilic bile acids such
as ursodeoxycholic acid, with the distinct ability to specifically
bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic
disorders such as cholestasis, NASH, and inflammatory bowel disease.