Cyanohydrin based fluorescent substrates of sEH (RMI)

sEH (RMI) 氰醇基荧光底物

• 批准号: 6879793
• 负责人: CHRISTOPHE HP MORISSEAU
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2005-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879793
• 关键词: affinity chromatography; animal tissue; antihypertensive agents; bioassay; biotechnology; chemical registry /resource; chemical synthesis; combinatorial chemistry; drug screening /evaluation; enzyme inhibitors; enzyme substrate; epoxide hydrolase; fluorescent dye /probe; high throughput technology; human tissue; hydrolysis; ionophores; liquid chromatography mass spectrometry; nonenzyme proteolytic agent; pharmacokinetics; prodrugs; radiochemistry; technology /technique development

DESCRIPTION (provided by applicant): Recent findings indicate that increasing the in vivo levels of arachidonic acid epoxides (EEl's) appears to be a new and excellent means to treat both hypertension and vascular inflammation. We have demonstrated that in vivo inhibition of soluble epoxide hydrolase (sEH) resulted in higher levels of EETs and in the reduction of blood pressure and inflammation in animal models. Because the effectiveness and length of action were less than optimal for the first generation of sEH inhibitors, the overall objective of our current work is to develop sEH inhibitors or prodrugs with improved r in vivo potency. Towards this end, we will first produce a fluorescent assay for sEH based on the liberation of cyanohydrin upon epoxide hydrolysis. The assay will be optimized toward establishing a high throughput screen in 96- and 384-well formats. The assay will be validated against our library of sEH inhibitors and a larger commercial combinatorial library. Ultimately, this assay will be used to develop new potent inhibitors of sEH. This will be done by screening the combinatorial libraries from the "NIH Roadmap", libraries contracted from commercial vendors, and more defined libraries generated in house.

描述（由申请人提供）：最近的发现表明，增加体内蛛网膜酸环氧化物（EEL）的水平似乎是治疗高血压和血管炎症的一种新的和出色的方法。 我们已经证明，在体内抑制可溶性环氧水解酶（SEH）导致较高的EET和动物模型中血压和炎症的减少。 由于对第一代SEH抑制剂的有效性和作用长度不足以最佳，因此我们当前工作的总体目标是开发具有改善R IN VIVO效力的SEH抑制剂或前药。 为此，我们将基于环氧化物水解后的氰氢化蛋白的释放，首先产生SEH的荧光测定。该测定法将优化，以建立96孔和384孔格式的高吞吐量屏幕。 该测定法将对我们的SEH抑制剂图书馆和更大的商业组合图书馆进行验证。 最终，该测定法将用于开发新的SEH有效抑制剂。 这将通过从“ NIH路线图”，从商业供应商签约的图书馆以及房屋中生成的更明确的图书馆中筛选组合图书馆来完成。