TY - JOUR T1 - LKY-047: First Selective Inhibitor of Cytochrome P450 2J2 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 765 LP - 769 DO - 10.1124/dmd.117.075036 VL - 45 IS - 7 AU - Nguyen Minh Phuc AU - Zhexue Wu AU - Yuseok O AU - Jee-Hyun Lee AU - Sangtaek Oh AU - Gyu-Yong Song AU - Kwang-Hyeon Liu Y1 - 2017/07/01 UR - http://dmd.aspetjournals.org/content/45/7/765.abstract N2 - Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7S)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole O-demethylase and terfenadine hydroxylase activity, with Ki values of 0.96 and 2.61 μM, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a Ki value of 3.61 μM. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC50 > 50 μM). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays. ER -