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, C., Finamore, C., Silvia Marchiano, †., Di Leva, F.S., Carino, A., Monti, M.C., del Gaudio, F., Ceccacci, S., Limongelli, V., Zampella, A., Fiorucci, S., DE MARINO, S.. - 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 FestaPrimo
;Claudia FinamoreSecondo
;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.| File | Dimensione | Formato | |
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Investigation-around-the-Oxadiazole-Core-in-the-Discovery-of-a-New-Chemotype-of-Potent-and-Selective-FXR-Antagonists2019ACS-Medicinal-Chemistry-Letters (7).pdf
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