Development of dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors as a Promising Therapeutic Strategy for the Treatment of Acute and Chronic Pain

项目摘要/摘要 我们的目标是开发将要使用的双可溶性环氧化物水解酶/脂肪酸酰胺水解酶抑制剂。 作为一种很有前途的新型治疗策略，在疼痛治疗中具有重要意义。我们将研究一系列苯并噻唑- 苯基哌啶类似物，对两种靶标酶都有很强的抑制作用，而且是代谢的 在肝微粒体中稳定。我们计划研究的化合物代表了一种亟需的、完全新颖的 非阿片类药物，疼痛管理研究的起点。因为这个类有不同的生物目标 现有的止痛药，它代表着一个解决长期存在的问题的机会，这些问题一直与 疼痛管理方面的现有疗法。在这个项目中，我们提出了对两者的同时调节 可溶性环氧化物水解酶(SEH)和脂肪酸酰胺水解酶(FAAH)可被双重抑制剂所抑制。 预计将在这一治疗策略的成功中发挥重要作用。我们知道，联合管理 在几种疼痛动物模型中，SEH和FAAH抑制剂显著减轻疼痛。然而，这一前景看好 这两种酶的双重抑制剂作为非阿片类止痛药的策略尚未得到有力的研究 发展方式。这种新型的非阿片类止痛药提供了灵活性和在 药物化学领域可能会克服目前可用的疼痛治疗中的弱点。最多的 这些化合物的原始和机械上不同的方面是它们能够同时抑制两个 在疼痛和炎症中起重要作用的不同酶。总体而言，结构组合- 本提案中的活动关系研究和计算方法将使详细的描述成为可能 这些新配体的双重抑制所需的分子决定因素。这最终将允许 开发有效且代谢稳定的sEH/FAAH双重抑制剂。这样的分子将对 与目前的阿片类药物相比，作为疼痛管理疗法的研究具有可预见的更好的临床特征 和非阿片类药物。

Project Summary/Abstract We aim to develop dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors that will be used as a promising novel therapeutic strategy in the pain management. We will study a series of benzothiazole- phenyl piperidine analogs which exhibit potent inhibition at both targeted enzymes, and that are metabolically stable in liver microsomes. The compounds we propose to study represent a much-needed, completely novel, nonopioid, starting point in pain management research. Because this class has different biological targets from existing analgesics, it represents an opportunity to solve long-standing problems that have been linked to the existing therapies in pain management. In this project we propose that the simultaneous regulation of the two enzymes, soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), by dual inhibitors, can be expected to play a significant role in the success of this therapeutic strategy. We know that co-administration of sEH and FAAH inhibitors significantly reduces pain in several animal models of pain. However, this promising strategy of dual inhibitors of both enzymes has not been robustly investigated as a nonopioid pain medication development approach. This novel class of nonopioid analgesics provides flexibility and an advance in the medicinal chemistry space that may overcome weaknesses in the currently available pain treatments. The most original and mechanistically distinct aspect of these compounds is their ability to simultaneously inhibit two different enzymes that play significant roles in pain and inflammation. Overall, the combination of structure- activity relationship studies and computational approaches in this proposal will enable a detailed characterization of the molecular determinants required for dual inhibition of these novel ligands. This will ultimately allow the development of potent and metabolically stable dual sEH/FAAH inhibitors. Such molecules will be valuable to study as pain management therapeutics with predictably superior clinical profiles as compared to current opioid and nonopioid drugs.