Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01640
Keywords
-
Categories
Funding
- National Institute of General Medical Sciences of the National Institutes of Health [R35GM118041]
- ALSAC
Ask authors/readers for more resources
In this study, a selective and potent PXR antagonist was discovered through structural optimization of a series of compounds. This finding provides novel PXR inhibitors for basic research and future clinical studies and sheds light on reducing compound's binding affinity to PXR.
The pregnane X receptor (PXR) is a key regulator of drug metabolism. Many drugs bind to and activate PXR, causing adverse drug responses. This suggests that PXR inhibitors have therapeutic value, but potent PXR inhibitors have so far been lacking. Herein, we report the structural optimization of a series of 1H-1,2,3-triazole-4-carboxamides compounds that led to the discovery of compound 85 as a selective and the most potent inverse agonist and antagonist of PXR, with low nanomolar IC50 values for binding and cellular activity. Importantly, compound 89, a close analog of 85, is a selective and pure antagonist with low nanomolar IC50 values for binding and cellular activity. This study has provided novel, selective, and most potent PXR inhibitors (a dual inverse agonist/antagonist and a pure antagonist) for use in basic research and future clinical studies and also shed light on how to reduce the binding affinity of a compound to PXR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available