期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 11, 页码 2919-2938出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.04.014
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资金
- American Lebanese Syrian Associated Charities (ALSAC)
- St. Jude Children's Research Hospital (St. Jude)
- National Institute of General Medical Sciences [GM086415]
- National Cancer Institute [P30-CA21765]
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. (C) 2014 Elsevier Ltd. All rights reserved.
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