N-1H-Benzimidazol-5-ylbenzenesulfonamide derivatives as potent hPXR agonists

作者：Benod Cindy; Subra Guy; Nahoum Virginie; Mallavialle Aude; Guichou Jean Francois; Milhau Julien; Robles Samuel; Bourguet William; Pascussi Jean Marc; Balaguer Patrick; Chavanieu Alain^*

来源：Bioorganic & Medicinal Chemistry, 2008, 16(7): 3537-3549.

DOI：10.1016/j.bmc.2008.02.020

• nuclear receptor
• hPXR
• docking
• drug design

The Human Pregnane X Receptor (hPXR) is a nuclear receptor that regulates the expression of phase I and phase II drug-metabolizing enzymes, as well as that of drug transporters. Because this receptor plays a critical role in protecting tissues from potentially toxic endo-and xenobiotics, highly active agonists could represent novel therapeutic tools in treating several human diseases. Using an in vitro screening reporter system that allow to characterize hPXR activators and a first step of chemical modifications of an original agonist ligand (C2BA-4, 1-(2-chlorophenyl)-N-[1-(1-phenylethyl)-1H-benzimidazol-5-yl] methanesulfonamide), we identified compounds with a N-1H-benzimidazol-5-ylbenzenesulfonamide scaffold as a potent family of hPXR agonists. Further chemical modi. cations allowed us to identify enhanced activators, notably N-(1-benzyl-1H-benzimidazol-5-yl)-2,3,4,5,6-pentamethylbenzenesulfonamide (6n) with an EC50 value in the subnanomolar range. Accordingly to their potent EC50, these compounds induced an efficient protection of hPXR against proteolytic digestion by trypsin even at very low ligand concentrations and were able to induce the expression of the main target genes of hPXR, CYP3A4 and CYP2B6, in primary cultures of human hepatocytes.

• 出版日期2008-4-1