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.

项目概要/摘要 我们的目标是开发双可溶性环氧化物水解酶/脂肪酸酰胺水解酶抑制剂，用于 作为疼痛管理中一种有前途的新型治疗策略。我们将研究一系列苯并噻唑- 苯基哌啶类似物对两种靶酶均表现出有效的抑制作用，并且在代谢上 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、全新的、 非阿片类药物，疼痛管理研究的起点。因为该类别具有与其他类别不同的​​生物靶标 与现有的镇痛药相比，它代表了解决与镇痛有关的长期存在的问题的机会 现有的疼痛管理疗法。在这个项目中，我们建议同时监管两个 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 预计将在该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 抑制剂可显着减轻多种疼痛动物模型的疼痛。然而，这个充满希望的 两种酶的双重抑制剂策略尚未作为非阿片类止痛药进行深入研究 发展方式。这类新型非阿片类镇痛药提供了灵活性并在治疗方面取得了进步 药物化学空间可以克服目前可用的疼痛治疗的弱点。最 这些化合物的原始和机械上不同的方面是它们能够同时抑制两种 在疼痛和炎症中发挥重要作用的不同酶。总体而言，结构的组合- 本提案中的活动关系研究和计算方法将能够进行详细的表征 这些新型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双重 sEH/FAAH 抑制剂。这样的分子将有价值 研究作为疼痛管理疗法，与目前的阿片类药物相比，具有可预测的优越临床特征 和非阿片类药物。