Inhibitory effects of phthalimide derivatives on the activity of the hepatic cytochrome P450 monooxygenases CYP2C9 and CYP2C19.
Affecting hepatic cytochrome (CYP) activity is one of the major concerns in drug-drug interaction. Thus the testing of drug candidates on their impact on these enzymes is an essential step in early drug discovery. We tested a collection of 480 in-house phthalimide derivatives against different CYP450s using a high throughput inhibition assay. In initial tests with the isoform CYP2C19 about 57.5% of the tested phthalimide derivatives showed significantly enhanced inhibitory effects against this enzyme. In addition similar patterns of phthalimide inhibition for CYP2C9 and CYP2C19 were found, whereas the unrelated isoforms CYP2D6 and CYP3A4 were not specifically affected. Also less than 10% of randomly chosen substances inhibited CYP2C9. Analyses of structure-function relationships revealed that the substituent at the nitrogen atom in the isoindole ring is of crucial impact for the activity of CYP2C9/19.
Kolukisaoglu
Üner
Ü
Center for Life Science Automation, University of Rostock, Friedrich-Barnewitz-Strasse 8, Rostock, Germany. uener.kolukisaoglu@celisca.de
Wendler
Christian
C
Goerdes
Dirk
D
Diener
Annette
A
Thurow
Kerstin
K
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology*; D010797:Phthalimides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010797:Phthalimides; D054852:Small Molecule Libraries; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19