LKY-047：细胞色素P450 2J2的首个选择性抑制剂。
LKY-047: First Selective Inhibitor of Cytochrome P450 2J2.
作者信息
Phuc Nguyen Minh, Wu Zhexue, O Yuseok, Lee Jee-Hyun, Oh Sangtaek, Song Gyu-Yong, Liu Kwang-Hyeon
机构信息
BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Department of Bio and Fermentation Convergence Technology, BK21 PLUS Program, Kookmin University, Seoul, Korea (S.O.).
BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Department of Bio and Fermentation Convergence Technology, BK21 PLUS Program, Kookmin University, Seoul, Korea (S.O.)
出版信息
Drug Metab Dispos. 2017 Jul;45(7):765-769. doi: 10.1124/dmd.117.075036. Epub 2017 May 1.
Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro--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 -demethylase and terfenadine hydroxylase activity, with values of 0.96 and 2.61 M, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a value of 3.61 M. 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 (IC > 50 M). 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.
目前尚无适用于反应表型分析的高选择性细胞色素P450 CYP2J2（CYP2J2）抑制剂。合成了一种去甲莪术素衍生物（7）-（+）-（4-硝基苯基）丙烯酸8,8-二甲基-2-氧代-6,7-二氢-吡喃并[3,2-g]色烯-7-基酯（LKY-047），并评估了其对人肝微粒体（HLM）中CYP2J2以及其他细胞色素P450（P450）酶的抑制效力。结果表明，LKY-047是CYP2J2介导的阿司咪唑去甲基酶和特非那定羟化酶活性的强效竞争性抑制剂，其抑制常数（Ki）值分别为0.96和2.61 μM。它还是CYP2J2介导的依巴斯汀羟化反应的非竞争性抑制剂，Ki值为3.61 μM。LKY-047与HLMs和NADPH预孵育不会改变抑制效力，表明它不是基于机制的抑制剂。发现LKY-047是一种选择性CYP2J2抑制剂，对其他人类P450酶（如CYP 1A2、2A6、2B6、2C8、2C9、2C19、2D6、2E1和3A）无抑制作用（IC50>50 μM）。这些体外数据支持将LKY-047用作选择性CYP2J2抑制剂，在反应表型分析试验中可能用于鉴定负责药物代谢的P450同工酶。
Zotero 插件