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 = 400 nM). 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 groups, respectively, are selective CYP2J2 inhibitors. Compound 4 is a high-affinity, competitive inhibitor and alternative substrate of CYP2J2 (K i = 160 ± 50 nM). Compound 5 and 13 are efficient mechanism-based inhibitors of CYP2J2 (k inact /K I values ~3000 L.mol −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.

Selective Inhibitors of CYP2J2 Related to Terfenadine Exhibit Strong Activity against Human Cancers in Vitro and in Vivo

“…The design and synthesis of high-affinity and selective CYP2J2 inhibitors derived from terfenadone, a derivative of the drug terfenadine, have been described in detail by Lafite et al (2007). We synthesized three of these compounds (compounds 4, 5, and 11), and an additional novel compound, which we have labeled compound 26 (C26), as hydrochloride jpet.aspetjournals.org salts.…”

“…Derivatives of the drug terfenadine were shown recently to be selective, high-affinity inhibitors of human CYP2J2 (Lafite et al, 2006(Lafite et al, , 2007. However, the role of these inhibitors in ameliorating EET-mediated promotion of the neoplastic phenotype has yet to be examined.…”

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

“…While a crystal structure has yet to be elucidated, molecular models suggest structural similarity between CYP2J2 and CYP3A4, explaining why the two enzymes share a number of substrates of diverse therapeutic areas, such as the antihistamine drugs terfenadine, astemizole, and ebastine (Matsumoto and Yamazoe, 2001;Hashizume et al, 2002;Matsumoto et al, 2002;Liu et al, 2006;Lafite et al, 2007), anticancer drug tamoxifen, and drugs such as thioridazine or cyclosporine (Lee et al, 2012). The combination of cardiac localization and involvement in the arachidonic acid metabolism makes CYP2J2 a particularly interesting target to mechanistically investigate drug-induced cardiotoxicity.…”

“…However, a human heart model remains elusive and testing relies on animal-model, especially dog, cell systems or recombinant enzymes. Much of CYP2J2's activity has been assessed in such models as Escherichia coli-expressed or Baculovirus-infected insect cell-expressed enzyme (Supersomes) (Lafite et al, 2007), human liver microsomes (Lee et al, 2012), or in humanized animal models that overexpress the enzyme in cardiac tissue (Seubert et al, 2004;Deng et al, 2011).…”

Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2

“…Moreover, terfenadine [12,13] and ebastine [13] have been used as the parent compounds to generate structure-based CYP2J2 inhibitors with K(i) values as low as 160 nM [12,13].…”