Activation of FXR receptor has shown effective in several liver injury. In this study, starting from GW4064, the first non-steroidal FXR ligand, we have elaborated and synthesized a library of derivates in order to improve the agonistic activity on FXR and the ADME properties. Maintaining the central isoxazole core with the 2,6-dichloro-substituted phenyl moiety at C-3 and the isopropyl group at C-5 we have introduced on the oxymethylene at C-4 different phenols using Mitsunobu reactions. The pharmacological characterization and molecular docking studies for the structure−acqvity raqonalizaqon, allowed the idenqficaqon of several FXR agonists. Compound 17 has been proved the most promising lead of this library, combining good pharmacokinetic properties with interesting FXR activity in vivo, and preventing acetaminopheninduced liver injury in mice.

Design, synthesis and pharmacological characterization of novel potent nonsteroidal agonists of the farnesoid X receptor

Valentina Sepe;Claudia Finamore;Giuliana Baronissi;Francesco Saverio Di Leva;Chiara Cassiano;Ettore Novellino;Vittorio Limongelli;Angela Zampella
2019

Abstract

Activation of FXR receptor has shown effective in several liver injury. In this study, starting from GW4064, the first non-steroidal FXR ligand, we have elaborated and synthesized a library of derivates in order to improve the agonistic activity on FXR and the ADME properties. Maintaining the central isoxazole core with the 2,6-dichloro-substituted phenyl moiety at C-3 and the isopropyl group at C-5 we have introduced on the oxymethylene at C-4 different phenols using Mitsunobu reactions. The pharmacological characterization and molecular docking studies for the structure−acqvity raqonalizaqon, allowed the idenqficaqon of several FXR agonists. Compound 17 has been proved the most promising lead of this library, combining good pharmacokinetic properties with interesting FXR activity in vivo, and preventing acetaminopheninduced liver injury in mice.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/787242
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