title: 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.
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.
authors.affiliation: TES Pharma S.r.l. , Via Palmiro Togliatti 22bis, I-06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.affiliation: TES Pharma S.r.l. , Via Palmiro Togliatti 22bis, I-06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.affiliation: TES Pharma S.r.l. , Via Palmiro Togliatti 22bis, I-06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Franco
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Mostarda
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Filipponi
authors.affiliation: TES Pharma S.r.l. , Via Palmiro Togliatti 22bis, I-06073 Loc. Terrioli, Corciano, Perugia, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Colliva
authors.affiliation: Interdisciplinary Department of Medicine, University of Bari , Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors.forename: Raffaella Maria
authors.initials: RM
authors.lastname: Gadaleta
authors.affiliation: Department of Chemistry, University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Placido
authors.initials: P
authors.lastname: Franco
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Department of Chemistry, University of Bologna , Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Roda
authors.affiliation: Interdisciplinary Department of Medicine, University of Bari , Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia , Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello