Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor.
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.
Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address: dyu@coh.org.
Donna D
DD
Yu
Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Wenwei
W
Lin
Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Barry M
BM
Forman
Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: taosheng.chen@stjude.org.
Taosheng
T
Chen
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
D000577:Amides; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated