title: Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2.
abstract: Twenty five derivatives of the drugs terfenadine and ebastine have been designed, synthesized and evaluated as inhibitors of recombinant human CYP2J2. Compound 14, which has an imidazole substituent, is a good non-competitive inhibitor of CYP2J2 (IC(50)=400nM). It is not selective towards CYP2J2 as it also efficiently inhibits the other main vascular CYPs, such as CYP2B6, 2C8, 2C9 and 3A4; however, it could be an interesting tool to inhibit all these vascular CYPs. Compounds 4, 5 and 13, which have a propyl, allyl and benzo-1,3-dioxole terminal group, respectively, are selective CYP2J2 inhibitors. Compound 4 is a high-affinity, competitive inhibitor and alternative substrate of CYP2J2 (K(i)=160+/-50nM). Compounds 5 and 13 are efficient mechanism-based inhibitors of CYP2J2 (k(inact)/K(i) values approximately 3000Lmol(-1)s(-1)). Inactivation of CYP2J2 by 13 is due to the formation of a stable iron-carbene bond which occurs upon CYP2J2-catalyzed oxidation of 13 with a partition ratio of 18+/-3. These new selective inhibitors should be interesting tools to study the biological roles of CYP2J2.
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 Université Paris Descartes, CNRS, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lafite
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dijols
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dansette
authors.forename: Daniel
authors.initials: D
authors.lastname: Mansuy
mesh_terms: D003198:Computer Simulation; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000648:ultrastructure*; D004347:Drug Interactions; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004795:Enzyme Stability; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010105:Oxygenases / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*
chemical_list: C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2