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

开发双可溶性环氧化物水解酶/脂肪酸酰胺水解酶抑制剂作为治疗急性和慢性疼痛的有前途的治疗策略

• 批准号: 10152621
• 负责人: Stevan Pecic
• 金额: $ 14.2万
• 依托单位: CALIFORNIA STATE UNIVERSITY FULLERTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152621
• 关键词: Absence of pain sensation; Acids; Acute Pain; Adverse effects; Analgesics; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Biochemistry; Biological; Biological Assay; Biomedical Research; Body part; Brain; California; Chemicals; Chemistry; Clinical; Data; Development; Drug Design; Drug Kinetics; Endocannabinoids; Enzymes; Epoxide hydrolase; Exhibits; FAAH inhibitor; Foundations; Funding; Future; Gastric ulcer; Goals; Health Professional; Human; In Vitro; Inflammation; Investigation; Laboratories; Lead; Libraries; Ligands; Link; Liver; Liver Microsomes; Medical; Medicine; Metabolic; Metabolism; Methodology; Methods; Modification; Molecular; Mus; Non-Steroidal Anti-Inflammatory Agents; Opioid; Opioid Receptor; Opioid agonist; Oxycodone; Pain; Pain management; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physical Dependence; Play; Rattus; Regulation; Research; Role; Series; Structure-Activity Relationship; Students; System; Testing; Therapeutic; Underrepresented Minority; Universities; addiction; analog; base; benzothiazole; chronic pain; design; drug discovery; endogenous opioids; fatty acid amide hydrolase; flexibility; improved; in silico; in vivo; inhibitor/antagonist; kidney dysfunction; liver injury; minority student; multidisciplinary; non-opioid analgesic; novel; novel therapeutic intervention; pain model; pain reduction; pain relief; pharmacophore; piperidine; preclinical development; scaffold; small molecule; success; treatment strategy

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.

项目摘要/摘要 我们旨在开发将使用的双重可溶性环氧化物水解酶/脂肪酸酰胺水解酶抑制剂 作为疼痛管理中有前途的新型治疗策略。我们将研究一系列苯噻唑唑 - 苯基哌啶类似物在两个靶向酶都表现出有效抑制作用，并且是代谢的 在肝微粒体中稳定。我们建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。因为该课程与 现有的镇痛药，它代表了解决与之相关的长期存在问题的机会 疼痛管理中的现有疗法。在这个项目中，我们建议同时对两者进行调节 双重抑制剂的酶，可溶性环氧化物水解酶（SEH）和脂肪酸酰胺水解酶（FAAH）可以是 预计将在这种治疗策略的成功中发挥重要作用。我们知道共同管理 SEH和FAAH抑制剂可显着减轻几种疼痛动物模型的疼痛。但是，这很有希望 两种酶的双重抑制剂的策略尚未作为非阿片类止痛药的重复研究 发展方法。这种新颖的非阿片类镇痛药提供了灵活性和进步 药物化学空间可能会克服当前可用的疼痛治疗中的弱点。最多 这些化合物的原始和机械上不同的方面是它们同时抑制两个的能力 在疼痛和炎症中起重要作用的不同酶。总体而言，结构的组合 - 该提案中的活动关系研究和计算方法将实现详细的特征 这些新型配体双重抑制所需的分子决定因素。这最终将允许 开发有效和代谢稳定的双SEH/FAAH抑制剂。这样的分子对于 与当前的阿片类药物相比，研究作为具有可预测的优质临床特征的疼痛管理治疗药 和非阿片类药物。