N-1H-benzimidazol-5-ylbenzenesulfonamide derivatives as potent hPXR agonists.
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.
Benod
Cindy
C
INSERM, U554, Montpellier, F-34090, Univ Montpellier 1 and 2, CNRS, UMR5048, Centre de Biochimie Structurale, Montpellier F-34090, France.
Subra
Guy
G
Nahoum
Virginie
V
Mallavialle
Aude
A
Guichou
Jean-François
JF
Milhau
Julien
J
Roblés
Samuel
S
Bourguet
William
W
Pascussi
Jean-Marc
JM
Balaguer
Patrick
P
Chavanieu
Alain
A
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
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