1. 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.
- Author
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Pellicciari, Roberto, Passeri, Daniela, De Franco, Francesca, Mostarda, Serena, Filipponi, Paolo, Colliva, Carolina, Gadaleta, Raffaella Maria, Franco, Placido, Carotti, Andrea, Macchiarulo, Antonio, Roda, Aldo, Moschetta, Antonio, and Gioiello, Antimo
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DEOXYCHOLIC acid , *FARNESOID X receptor , *BILE acids , *HYDROXYL group , *HYDROXYLATION , *STRUCTURE-activity relationship in pharmacology - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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