Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2.
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.
Lafite
Pierre
P
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 Université Paris Descartes, CNRS, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Dijols
Sylvie
S
Zeldin
Darryl C
DC
Dansette
Patrick M
PM
Mansuy
Daniel
D
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*
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