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

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 ?M, respectively). The excellent pharmacokinetic properties make compound 3f the most promising lead identified in this study.

SUBMITTER: Festa C

PROVIDER: S-EPMC6466555 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Festa Carmen C Finamore Claudia C Marchianò Silvia S Di Leva Francesco Saverio FS Carino Adriana A Monti Maria Chiara MC Del Gaudio Federica F Ceccacci Sara S Limongelli Vittorio V Zampella Angela A Fiorucci Stefano S De Marino Simona S

ACS medicinal chemistry letters 20190110 4

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 ...[more]

PMID: 30996787

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