sEH Inhibitors to Treat Neuropathic Pain

 描述(申请人提供)：通过这项建议，我们的目标是进一步开发新型和安全的sEH口服抑制剂，用于治疗糖尿病患者的周围神经病变。我们候选的EC5026的临床前研究证明了对糖尿病神经病变的疗效。EicOsis选择了EC5026，因为它的疗效和良好的PK/ADME特性和稳定性，将进入这一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化合物对一系列酶的脱靶作用，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风险降低测试。EicOsis已将这些数据用作应用程序的基础，以便与Blueprint开发团队合作创建开发计划并启动研究，以在第一阶段临床试验中测试EC5026的安全性。为了进一步开发从完成的第一阶段应用中挑选出来的化合物，我们建议在这里对候选和备用化合物进行放射性标记，以进行详细的新陈代谢研究，并开发该标签作为人类第一阶段临床试验的示踪剂。此外，我们建议使用常规材料来测试体内的脱靶毒性。 并探索这些抑制剂在交替疼痛模型中的活性广度。这些研究旨在解决了解新陈代谢和活动光谱的问题，如果缺乏，往往会阻碍药物的开发。这一结果将为制药行业的科学家提供关键数据，这些数据表明sEH抑制剂作为未来止痛剂的活性范围更广。

 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.