title: N-1H-benzimidazol-5-ylbenzenesulfonamide derivatives as potent hPXR agonists.
abstract: 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 modifications allowed us to identify enhanced activators, notably N-(1-benzyl-1H-benzimidazol-5-yl)-2,3,4,5,6-pentamethylbenzenesulfonamide (6n) with an EC(50) value in the subnanomolar range. Accordingly to their potent EC(50), 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.
authors.affiliation: INSERM, U554, Montpellier, F-34090, Univ Montpellier 1 and 2, CNRS, UMR5048, Centre de Biochimie Structurale, Montpellier F-34090, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Benod
authors.forename: Guy
authors.initials: G
authors.lastname: Subra
authors.forename: Virginie
authors.initials: V
authors.lastname: Nahoum
authors.forename: Aude
authors.initials: A
authors.lastname: Mallavialle
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Guichou
authors.forename: Julien
authors.initials: J
authors.lastname: Milhau
authors.forename: Samuel
authors.initials: S
authors.lastname: Roblés
authors.forename: William
authors.initials: W
authors.lastname: Bourguet
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Pascussi
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Alain
authors.initials: A
authors.lastname: Chavanieu
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics; D011987:Receptors, Steroid / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D013449:Sulfonamides; C528601:N-1H-benzimidazol-5-ylbenzenesulfonamide; D000096926:Benzenesulfonamides; C585599:CYP2B6 protein, human; C510163:CYP3A4 protein, human