...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemical Pharmacology >Covalent inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by the carbamates JZL184 and URB597
【24h】

Covalent inhibition of recombinant human carboxylesterase 1 and 2 and monoacylglycerol lipase by the carbamates JZL184 and URB597

机译：氨基甲酸酯JZL184和URB597共价抑制重组人羧酸酯酶1和2和单酰基甘油脂酶

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Carboxylesterase type 1 (CES1) and CES2 are serine hydrolases located in the liver and small intestine. CES1 and CES2 actively participate in the metabolism of several pharmaceuticals. Recently, carbamate compounds were developed to inhibit members of the serine hydrolase family via covalent modification of the active site serine. URB597 and JZL184 inhibit fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively; however, carboxylesterases in liver have been identified as a major off-target. We report the kinetic rate constants for inhibition of human recombinant CES1 and CES2 by URB597 and JZL184. Bimolecular rate constants (k inact/ K i) for inhibition of CES1 by JZL184 and URB597 were similar [3.9 (±0.2) × 10 3 M -1 s -1 and 4.5 (±1.3) × 10 3 M -1 s -1, respectively]. However, k inact/K i for inhibition of CES2 by JZL184 and URB597 were significantly different [2.3 (±1.3) × 10 2 M -1 s -1 and 3.9 (±1.0) × 10 3 M -1 s -1, respectively]. Rates of inhibition of CES1 and CES2 by URB597 were similar; however, CES1 and MAGL were more potently inhibited by JZL184 than CES2. We also determined kinetic constants for spontaneous reactivation of CES1 carbamoylated by either JZL184 or URB597 and CES1 diethylphosphorylated by paraoxon. The reactivation rate was significantly slower (4.5×) for CES1 inhibited by JZL184 than CES1 inhibited by URB597. Half-life of reactivation for CES1 carbamoylated by JZL184 was 49 ± 15 h, which is faster than carboxylesterase turnover in HepG2 cells. Together, the results define the kinetics of inhibition for a class of drugs that target hydrolytic enzymes involved in drug and lipid metabolism.
机译：1型羧酸酯酶（CES1）和CES2是位于肝脏和小肠的丝氨酸水解酶。 CES1和CES2积极参与多种药物的代谢。最近，开发了氨基甲酸酯化合物以通过对活性位点丝氨酸的共价修饰来抑制丝氨酸水解酶家族的成员。 URB597和JZL184分别抑制脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂酶（MAGL）;然而，肝脏中的羧酸酯酶已被确定为主要的靶标。我们报告了URB597和JZL184抑制人重组CES1和CES2的动力学速率常数。 JZL184和URB597抑制CES1的双分子速率常数（k inact / K i）相似[3.9（±0.2）×10 3 M -1 s -1和4.5（±1.3）×10 3 M -1 s -1 ， 分别]。但是，JZL184和URB597抑制CES2的k inact / K i分别显着不同[2.3（±1.3）×10 2 M -1 s -1和3.9（±1.0）×10 3 M -1 s -1 ]。 URB597对CES1和CES2的抑制率相似。但是，JZL184比CES2对CES1和MAGL的抑制作用更强。我们还确定了JZL184或URB597氨基甲酸酯化的CES1的自发再活化和对氧磷对CES1二乙基磷酸化的动力学常数。 JZL184抑制的CES1的重活化速率显着低于URB597抑制的CES1的重活化速率（4.5倍）。 JZL184的氨基甲酸酯化的CES1复活的半衰期为49±15小时，比HepG2细胞中的羧酸酯酶转换更快。在一起，结果定义了针对靶向与药物和脂质代谢有关的水解酶的一类药物的抑制动力学。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号