sEH Inhibitors to Treat Neuropathic Pain

sEH 抑制剂治疗神经性疼痛

• 批准号: 9471107
• 负责人: Alan R Buckpitt
• 金额: $ 0.14万
• 依托单位: EICOSIS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9471107
• 关键词: Addictive Behavior; Address; Adverse effects; Analgesics; Aromatic Amines; Back; Benchmarking; Biological Assay; Biology; Blood - brain barrier anatomy; Brain; Carbon; Carbon Dioxide; Cardiotoxicity; Characteristics; Chemicals; Chemistry; Clinic; Cytochrome P450; Data; Development; Development Plans; Diabetic Neuropathies; Dose; Drug Industry; Drug usage; Enzyme Tests; Enzymes; Epoxide hydrolase; Equilibrium; Future; Goals; Grant; Hemostatic function; Human; Hyperalgesia; In Vitro; Inflammation; Label; Laboratories; Laboratory Research; Lesion; Locomotion; Malignant Neoplasms; Metabolism; Methods; Modeling; Monitor; Movement; Neuraxis; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; Opioid; Oral; Organ; Pain; Pain management; Penetration; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Postoperative Pain; Program Development; Property; Radiolabeled; Refractory; Research Contracts; Reserpine; Risk; Rodent; Route; Safety; Scientist; Small Business Innovation Research Grant; Speed; Testing; Therapeutic; Toxic effect; Toxicology; Tracer; United States National Institutes of Health; Urea; Work; accelerator mass spectrometry; base; clinical development; design; diabetic patient; drug candidate; fibromyalgia pain; gastrointestinal; in vivo; inhibitor/antagonist; metabolic abnormality assessment; novel; orofacial; painful neuropathy; phase 1 study; physical property; preclinical study; prevent; programs; public health relevance; radiotracer; safety testing; scale up

 DESCRIPTION (provided by applicant): With this proposal we aim to further the development of novel and safe oral inhibitors of sEH for the treatment of peripheral neuropathy in diabetic patients. Preclinical studies with our candidate EC5026 demonstrated efficacy for diabetic neuropathy. EicOsis has selected EC5026 for its efficacy with good PK/ADME properties and stability to enter further development stages for this indication. EicOsis also tested the compound and a backup in vitro for off target effects against an array of enzymes, determined the potential inhibition of major cytochrome P450 enzymes, and tested for de-risking with a contract research laboratory. EicOsis has used these data as a basis for an application to work with Blueprint Development Teams to create a development plan and initiate studies to test the safety of EC5026 in Phase 1 clinical trials. To further develop the compounds selected from the completed Phase I application we propose here to radiolabel the candidate and backup to carry out detailed metabolism studies and develop the label as a tracer for human Phase I clinical trial. Additionally we propose to use conventional material to test for off-target toxicity in vivo and to explore the breadth of activity of the inhibitors in alternate pain models. The studies are designed to address understanding metabolism and the spectrum of activity which if lacking often prevent drugs from being developed. The results will empower scientists in the pharmaceutical industry with critical data that speaks to the wider spectrum of activity of sEH inhibitors as analgesics of the future.

 描述（由申请人提供）：通过本提案，我们的目标是进一步开发新型安全的口服 sEH 抑制剂，用于治疗糖尿病患者的周围神经病变。我们的候选药物 EC5026 的临床前研究表明，EicOsis 对糖尿病神经病变具有疗效。因其良好的 PK/ADME 特性和稳定性而进入该适应症的进一步开发阶段，EicOsis 还在体外测试了该化合物和备用药物。针对一系列酶的脱靶效应，确定了主要细胞色素 P450 酶的潜在抑制作用，并与合同研究实验室进行了去风险测试，EicOsis 已将这些数据用作与蓝图开发团队合作创建的应用程序的基础。制定开发计划并启动研究以测试 EC5026 在 1 期临床试验中的安全性。为了进一步开发从已完成的 I 期申请中选择的化合物，我们在此建议对候选药物进行放射性标记，并进行备份以进行详细的代谢研究并开发标签。作为人类 I 期临床试验的示踪剂，我们建议使用常规材料来测试体内脱靶毒性。 并探索抑制剂在替代疼痛模型中的活性广度。这些研究旨在了解代谢和活性谱，如果缺乏这些活性谱，这些结果将为制药行业的科学家提供关键数据。这说明了 sEH 抑制剂作为未来镇痛药的广泛活性。

项目成果

Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative.

• DOI: 10.1021/acs.jmedchem.0c01886
• 发表时间: 2021-02-25
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Hammock BD;McReynolds CB;Wagner K;Buckpitt A;Cortes-Puch I;Croston G;Lee KSS;Yang J;Schmidt WK;Hwang SH
• 通讯作者: Hwang SH