title: Inhibition of human hepatic CYP isoforms by mGluR5 antagonists.
abstract: Characterization of new chemical entities for their potential to produce drug-drug interactions is an important aspect of early drug discovery screening. In the present study, the potential for three metabotropic glutamate receptor antagonists to interact with recombinant human CYPs was investigated. 2-Methyl-6-(phenylethenyl) pyridine (SIB-1893), 2-methyl-6-(phenylethynyl) pyridine (MPEP) and 3-[2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) were moderate competitive inhibitors of recombinant human CYP1A2 (Ki, 0.5-1 microM). SIB-1893, but not MPEP or MTEP, was also a moderate competitive inhibitor of CYP1B1. MPEP and MTEP were weak inhibitors of CYP2C19. None of the three compounds tested were significant inhibitors (IC(50) values >50 microM) of CYP3A4, 2C9, 2D6, 2A6, 2B6 or 2E1. The results suggest that MTEP is a selective inhibitor of CYP1A2 and may prove to be a useful tool in studying drug-drug interactions involving this enzyme.
authors.affiliation: Merck Research Laboratories San Diego, 3535 General Atomics Court, MRLSDB2, San Diego, CA 92121, USA. mitchell_green@merck.com
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Green
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jiang
authors.forename: Christopher D
authors.initials: CD
authors.lastname: King
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C578935:GRM5 protein, human; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C120148:SIB 1893; D013844:Thiazoles; C121465:6-methyl-2-(phenylethynyl)pyridine; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1