Design and Optimization of 1H-1,2,3-Triazole-4-carboxamides as Novel, Potent, and Selective Inverse Agonists and Antagonists of PXR

Abstract

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.

Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR

“…1e ) 17 , 21 , 27 . The increased region B interactions with both the π-trap and leucine cage likely account for the enhanced binding affinity of the amide series compared to the sulfonyl series 24 , 25 but may not be indicative of agonist/antagonist property. To specifically assess agonist/antagonist activities, we examined α12, which is a feature central to NR function 28 , 29 .…”

“…The ligand-α12 interface dictates PXR agonism and antagonism Since the discovery of SPA70 and its analogs as PXR antagonists and agonists 17,23,24 , we have described related compounds having an amide bond in lieu of the sulfonyl linkage found in SPA70, exemplified by SJPYT-310 (Fig. 1a) as a more potent PXR antagonist than SPA70 25 . Although there are >40 reported structures of PXR LBD bound to agonists 21 , including the SPA70 analog SJB7 (Fig.…”

“…However, using an unbiased high-throughput screening approach, we previously identified SPA70 as a potent and selective PXR antagonist with activity in vivo 17 , 23 . Surprisingly, subsequent structure-activity relationship studies revealed that subtle chemical changes convert SPA70 into an agonist 24 , and further derivatization yielded potent compounds of both agonist and antagonist classes 25 . Because the previous work was performed through empirical medicinal chemistry efforts, and there are no crystal structures of antagonist-bound PXR, it is currently unknown how seemingly insignificant chemical modifications result in such drastic antagonist-to-agonist activity switches.…”