Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor: virtual screening, synthesis, and biological evaluation.

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Deng G, Li W, Shen J, Jiang H, Chen K, Liu H

Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor: virtual screening, synthesis, and biological evaluation.

Bioorg Med Chem Lett. 2008 Oct 15;18(20):5497-502. doi: 10.1016/j.bmcl.2008.09.027. Epub 2008 Sep 10.

PubMed ID

18815030 [ View in PubMed

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Abstract

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 EC(50) 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).

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Chenodeoxycholic acid	Bile acid receptor	EC 50 (nM)	6310	N/A	N/A	Details