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

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 11; pp. 2919 - 2938
• Main Authors: Yu, Donna D., Lin, Wenwei, Forman, Barry M., Chen, Taosheng
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.06.2014; Elsevier
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; FXR; BSEP; BAs; SAR; HTS; Cyp7A1; NRs; LBD; CHOLESTEROL; LIGANDS; FXR ANTAGONIST; BIOLOGICAL EVALUATION; CHEMISTRY; AGONISTS; DERIVATIVES; BILE-ACIDS; DISCOVERY; NUCLEAR RECEPTOR
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.04.014

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 7.5nM in an FXR binding assay and 468.5nM 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.