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

ACS medicinal chemistry letters, 2019-04, Vol.10 (4), p.504-510 [Peer Reviewed Journal]

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Title:
Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists
Author: Festa, Carmen ; Finamore, Claudia ; Marchianò, Silvia ; Di Leva, Francesco Saverio ; Carino, Adriana ; Monti, Maria Chiara ; del Gaudio, Federica ; Ceccacci, Sara ; Limongelli, Vittorio ; Zampella, Angela ; Fiorucci, Stefano ; De Marino, Simona
Subjects: Letter
Is Part Of: ACS medicinal chemistry letters, 2019-04, Vol.10 (4), p.504-510
Description: 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.
Publisher: United States: American Chemical Society
Language: English
Identifier: ISSN: 1948-5875
EISSN: 1948-5875
DOI: 10.1021/acsmedchemlett.8b00534
PMID: 30996787
Source: Geneva Foundation Free Medical Journals at publisher websites
PubMed Central

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