Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists.

ID: ALA4433214

Journal: ACS Med Chem Lett

Title: Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists.

Authors: Festa C, Finamore C, Marchianò S, Di Leva FS, Carino A, Monti MC, Del Gaudio F, Ceccacci S, Limongelli V, Zampella A, Fiorucci S, De Marino S.

Abstract: Recent findings have shown that Farnesoid X Receptor (FXR) antagonists might be useful in the treatment of cholestasis and related metabolic disorders. In this paper, we report the discovery of a new chemotype of FXR antagonists featured by a 3,5-disubstituted oxadiazole core. In total, 35 new derivatives were designed and synthesized, and notably, compounds 3f and 13, containing a piperidine ring, displayed the best antagonistic activity against FXR with promising cellular potency (IC₅₀ = 0.58 ± 0.27 and 0.127 ± 0.02 μM, respectively). The excellent pharmacokinetic properties make compound 3f the most promising lead identified in this study.

CiteXplore: 30996787

DOI: 10.1021/acsmedchemlett.8b00534

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