The identification of a novel pyrazolidine-3,5-dione based scaffold hit compound as Farnesoid X receptor
(FXR) partial or full agonist has been accomplished by means of virtual screening techniques. A series of
pyrazolidine-3,5-dione derivatives (1a–u and 7) was designed, synthesized, and evaluated by a cell-based
luciferase transactivation assay for their agonistic activities against FXR. Most of them showed agonistic
potencies and 10 of them (1a, 1b, 1d–f, 1j, 1n, 1t, 5b, and 7) exhibited lower EC50 values than the reference
drug CDCA. Molecular modeling studies for the representative compounds 1a, 1d, 1f, 1j, 1n, 1u, 5b,
and 7 were also presented. The novel structural scaffold has provided a new direction for finding potent and selective
FXR partial and full agonists (referred to as ‘selective bile acid receptor modulators’, SBARMs).