Recent findings have demonstrated that FXR antagonists may be beneficial for treating cholestasis and related metabolic disorders.[56] In 2019, Festa et al. reported the discovery of a new chemotype of FXR antagonists featured by a 3,5‐disubstituted oxadiazole core.[140] A total of 35 new derivatives were designed and synthesized, and among them, compounds 63 and 64 (Figure 12), containing a protonable piperidine nucleus at C‐5 and a naphthyl group at C‐3, displayed the best antagonistic activity against FXR with promising cellular potency (IC50 0.58 ± 0.27 and 0.127 ± 0.02 μM, respectively). This evidence concerns the gene NR1H4 and metabolic disease.