2. Academic Validation
  3. Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor

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

  • Bioorg Med Chem. 2014 Jun 1;22(11):2919-38. doi: 10.1016/j.bmc.2014.04.014.
Donna D Yu 1,  Wenwei Lin 2,  Barry M Forman 3,  Taosheng Chen 4
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 4 Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: taosheng.chen@stjude.org.
PMID: 24775917 DOI: 10.1016/j.bmc.2014.04.014
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.

Figures
Products