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

Roberto Pellicciari, Daniela Passeri, Francesca De Franco, Serena Mostarda, Paolo Filipponi, Carolina Colliva, Raffaella Maria Gadaleta, Placido Franco, Andrea Carotti, Antonio Macchiarulo, Aldo Roda, Antonio Moschetta, Antimo Gioiello

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)9201-9214
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number19
DOIs
Publication statusPublished - Oct 13 2016

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Bile Acids and Salts
Acids
Ursodeoxycholic Acid
Cholestasis
Hydroxylation
Inflammatory Bowel Diseases
Pharmacology
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / 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; Gioiello, Antimo.

In: Journal of Medicinal Chemistry, Vol. 59, No. 19, 13.10.2016, p. 9201-9214.

Research output: Contribution to journalArticle

Pellicciari, R, Passeri, D, De Franco, F, Mostarda, S, Filipponi, P, Colliva, C, Gadaleta, RM, Franco, P, Carotti, A, Macchiarulo, A, Roda, A, Moschetta, A & Gioiello, A 2016, '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', Journal of Medicinal Chemistry, vol. 59, no. 19, pp. 9201-9214. https://doi.org/10.1021/acs.jmedchem.6b01126
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 ; Gioiello, Antimo. / 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. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 19. pp. 9201-9214.
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