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 / Sepe, Valentina; Finamore, Claudia; Baronissi, Giuliana; Di Leva, Francesco Saverio; Cassiano, Chiara; Monti, Maria Chiara; Novellino, Ettore; Limongelli, Vittorio; Fiorucci, Stefano; Zampella, Angela. - (2019), pp. 56-56. (Intervento presentato al convegno MedChem2019 IV annual COST ACTION CA15135 meeting Paul Ehrlich Euro-PhD Network & MuTaLig COST Action meeting 2019 tenutosi a Catanzaro (Italy) nel June 13th-15th 2019).
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;Maria Chiara Monti;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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
