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

项目概要/摘要 我们的目标是开发双重可溶性环氧化物水解酶/脂肪酸酰胺水解酶抑制剂， 作为一个有前途的新的治疗策略，在疼痛管理。我们将研究一系列苯并噻唑- 苯基哌啶类似物，其对两种靶向酶都表现出有效的抑制作用， 在肝微粒体中稳定。我们提议研究的化合物代表了一种急需的，完全新颖的， 非阿片类药物，疼痛管理研究的起点。因为这门课有不同的生物学目标， 现有的止痛药，它代表了一个机会，以解决长期存在的问题，已被链接到 现有的疼痛治疗方法。在这个项目中，我们建议同时调节这两个 酶，可溶性环氧化物水解酶（sEH）和脂肪酸酰胺水解酶（FAAH），通过双重抑制剂，可以被 预期在这种治疗策略的成功中发挥重要作用。我们知道， sEH和FAAH抑制剂在几种疼痛动物模型中显著减轻疼痛。然而，这一前景 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 发展方针。这类新的非阿片类镇痛药提供了灵活性，并在这方面取得了进展。 药物化学空间，可以克服目前可用的疼痛治疗的弱点。最 这些化合物最初的和机制上不同的方面是它们同时抑制两种 不同的酶在疼痛和炎症中起着重要作用。总的来说，结构的组合- 本提案中的活动关系研究和计算方法将能够详细描述 这些新的配体的双重抑制所需的分子决定因素。这将最终使 开发有效且代谢稳定的sEH/FAAH双重抑制剂。这样的分子将是有价值的 作为疼痛管理治疗剂的研究，与当前阿片类药物相比，具有可预测的上级临床特征 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.