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.

Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists / Festa, Carmen; Finamore, Claudia; Silvia Marchiano, †; Di Leva, Francesco Saverio; Carino, Adriana; Chiara Monti, Maria; del Gaudio, Federica; Ceccacci, Sara; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano; DE MARINO, Simona. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019), pp. 504-510. [10.1021/acsmedchemlett.8b00534]

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

Carmen Festa
Primo
;
Claudia Finamore
Secondo
;
Francesco Saverio Di Leva;Maria Chiara Monti;Vittorio Limongelli;Angela Zampella;Simona De Marino
Ultimo
2019

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.
2019
Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists / Festa, Carmen; Finamore, Claudia; Silvia Marchiano, †; Di Leva, Francesco Saverio; Carino, Adriana; Chiara Monti, Maria; del Gaudio, Federica; Ceccacci, Sara; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano; DE MARINO, Simona. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019), pp. 504-510. [10.1021/acsmedchemlett.8b00534]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/728308
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