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
- J Med Chem. 2016 Oct 13;59(19):9201-9214. doi: 10.1021/acs.jmedchem.6b01126.
- 1. TES Pharma S.r.l. , Via Palmiro Togliatti 22bis, I-06073 Loc. Terrioli, Corciano, Perugia, Italy.
- 2. Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, 06123 Perugia, Italy.
- 3. Interdisciplinary Department of Medicine, University of Bari , Piazza Giulio Cesare 11, 70124 Bari, Italy.
- 4. Department of Chemistry, University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
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.