• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>RSC Advances >Design and synthesis of uracil urea derivatives as potent and selective fatty acid amide hydrolase inhibitors
【24h】

Design and synthesis of uracil urea derivatives as potent and selective fatty acid amide hydrolase inhibitors

机译：设计和合成尿嘧啶脲衍生物作为有效和选择性的脂肪酸酰胺水解酶抑制剂

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Fatty acid amide hydrolase (FAAH) is one of the key enzymes involved in the biological degradation of endocannabinoids, especially anandamide. Pharmacological blockage of FAAH restores the levels of endocannabinoids, providing therapeutic benefits in the management of inflammation, depression and multiple sclerosis. In this study, a series of uracil urea derivatives as FAAH inhibitors were designed and synthesized. Structural modifications at the C5 position and side chain of N-hexyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-carboxamide (1a) led to FAAH inhibitors with improved potency and selectivity. Structure–activity relationship (SAR) studies indicated that C5 electron-withdrawing substituents were preferred for optimal potency but not for selectivity, whereas replacement of the alkyl chain with phenylalkyl moieties or biphenyl groups significantly improved both inhibitory potency and selectivity towards FAAH. Two highly potent picomolar FAAH inhibitors (4c, IC50 = 0.3 ± 0.05 nM; 4d, IC50 = 0.8 ± 0.1 nM) were developed. Compound 4c inhibited FAAH in a rapid, selective, noncompetitive, and irreversible pattern. This study provides several highly potent and selective FAAH inhibitors and an optimized chemical scaffold for the development of FAAH inhibitors. We anticipate that these FAAH inhibitors will enable new possibilities in understanding FAAH functions and development of therapeutics for pain and inflammatory diseases.
机译：脂肪酸酰胺水解酶（FAAH）是参与内源性大麻素（尤其是anandamide）生物降解的关键酶之一。 FAAH的药理学阻断作用可恢复内源性大麻素的水平，在控制炎症，抑郁和多发性硬化症方面提供治疗益处。在这项研究中，设计和合成了一系列尿嘧啶脲衍生物作为FAAH抑制剂。 N -己基-2,4-二氧代-3,4-二氢嘧啶-1（2 H ）-羧酰胺（1a）C5位置和侧链的结构修饰导致FAAH抑制剂的效能和选择性得到改善。结构-活性关系（SAR）研究表明，C5吸电子取代基优选具有最佳效能，但不具有选择性，而用苯基烷基基团或联苯基取代烷基链则可显着提高对FAAH的抑制效能和选择性。两种高效的皮摩尔FAAH抑制剂（4c，IC 50 = 0.3±0.05 nM; 4d，IC 50 = 0.8±0.1 nM）。化合物4c以快速，选择性，非竞争性和不可逆的方式抑制FAAH。这项研究提供了几种高效和选择性的FAAH抑制剂，以及为开发FAAH抑制剂而优化的化学支架。我们预计这些FAAH抑制剂将为了解FAAH功能和开发针对疼痛和炎性疾病的疗法提供新的可能性。

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