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.