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

Carmen Festa; Claudia Finamore; Silvia Marchianò; Francesco Saverio Di Leva; Adriana Carino; Maria Chiara Monti; Federica Del Gaudio; Sara Ceccacci; Vittorio Limongelli; Angela Zampella; Stefano Fiorucci; Simona De Marino

doi:10.1021/acsmedchemlett.8b00534

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

ACS Med Chem Lett. 2019 Jan 10;10(4):504-510. doi: 10.1021/acsmedchemlett.8b00534. eCollection 2019 Apr 11.

Affiliations

¹ Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, Naples 80131, Italy.
² Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia 06132, Italy.
³ Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, Fisciano, Salerno 84084, Italy.
⁴ Faculty of Biomedical Sciences, Institute of Computational Science - Center for Computational Medicine in Cardiology, Università della Svizzera italiana (USI), Via G. Buffi 13, Lugano CH-6900, Switzerland.

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.