Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

Abstract

Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5 nM in an FXR binding assay and 468.5 nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR.

Cholestatic Drug Induced Liver Injury: A Function of Bile Salt Export Pump Inhibition and Farnesoid X Receptor Antagonism

“…25 DY268 has been shown to be a potent FXR antagonist. 26 SCHH were prepared and treated with CsA (10 lM), or CDCA (30 lM) alone, CsA (10 lM) + CDCA (30 lM), Trog (100 lM) + CsA (10 lM) + CDCA (30 lM), or DY268 (5 lM) + CsA (10 lM) + CDCA (30 lM). Stock solutions were prepared as previously described.…”

“…4A). However, when Trog (100 lM) or DY268 (5 lM), a potent FXR antagonist, 26 was coincubated with CsA and CDCA, the response of FGF19 gene expression was decreased by 70% and 91%, respectively. Likewise, OSTb gene expression following treatment with Trog (100 lM) or DY268 (5 lM) in the presence of CsA and CDCA was decreased by 52% and 92%, respectively.…”

Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists

“…There are also a few synthetic non-steroidal scaffolds reported to date (Fig. 2), i.e., troglitazone ( 1 ) [31], substituted-isoxazole derivatives ( 2a–2b ) [32], 1, 3, 4-trisubstituted-pyrazolone ( 3 ) [33], T3 ( 4 ) [34], NDB ( 5 ) [35], hydroxyacetophenone derivatives ( 6a–6c ) [36] and 1,3-disubstituted-pyrazole-3-carboxamide ( 7a–7c ) [37]. Natural products derived antagonists are rarely known, and only a family of sesterterpene suvanine except GS [38].…”

Beyond Bile Acids: Targeting Farnesoid X Receptor (FXR) with Natural and Synthetic Ligands

“…Among these ligands, Ivermectin (59) was again identified as FXR modulator with an IC 50 of 0.26 μM, while Nimodipine (61) showed a weak partial agonist activity at the receptor with an IC 50 of 8.96 μM. More recently, the same authors applied their TR-FRET binding assay to discover novel FXR antagonists from the screening of a focused library of pyrazole substituted compounds [116]. As a result, they identified 1,3-disubstituted-pyrazole-4-carboxamide (62) as a potent FXR antagonist.…”