Engineered Neurotensin Fragments Targeting Neuropathic Pain

描述（由申请人提供）：神经性疼痛管理是一个主要的未满足的临床需求。经典使用的药物，包括阿片类药物和非阿片类药物（主要是NSAID），具有与其使用相关的主要副作用，许多人对任何药物都没有反应。正在寻求具有新作用机制的神经性疼痛药物作为替代方案;然而，唯一成功的FDA批准的靶向钙通道的药物对其广泛使用具有严重的限制。神经降压素（NT）及其完全活性片段NT（8- 13）已显示当集中给药时具有对抗神经性疼痛的显著活性;然而，在全身给药时未观察到活性。Halimed Pharmaceuticals已经设计了NT（8-13）衍生物，当IV给药（以及高浓度口服给药）时，这些衍生物表现出有效的镇痛活性。这些化合物是NT-受体激动剂，一种新的镇痛机制，因此它们可能没有目前批准的药物的限制。我们假设工程化的NT（8-13）衍生物可以被开发为新型神经性疼痛药物，其基础将通过在该I期申请中完成两个特定目的来提供。在具体目标1中，14种高效NT（8-13）衍生物将在神经性疼痛的标准Chung模型中通过IV和口服施用进行充分评价。还将测定与两种克隆和表达的大鼠和人NT受体（NTR）的体外效力/受体结合，以确定是否与体内结果相关;这将潜在地表明， 作用机制。将在模拟肠液和胃液、血浆和均质化脑制剂中测定每种化合物的总体稳定性（降解t1/2s）。这将使得能够评价在不同环境中的相对受体结合效力和/或半衰期之一或其组合是否可预测总体镇痛效果。 活动这三种最有效的化合物将进入特定目标2，其中将充分表征其药代动力学/药效学特性。PK/PD数据对于开发动物临床前毒性和安全性评价的研究设计、有效人体剂量预测以及最终临床试验设计至关重要。通过这一目标对三种化合物进行表征，将使该计划向前发展具有灵活性。该目标的完成将为II期申请的准备提供所需的基础，以通过临床前研究（合成、毒性等）开发铅。IND的准备和提交。本I期研究将在Halimed Pharmaceuticals进行，并与南卡罗来纳州医科大学的PI长期合作者克雷格比森博士合作。

DESCRIPTION (provided by applicant): Neuropathic pain management is a major unmet clinical need. Classically used medications, including opioids and non-opioids (primarily NSAIDs), have major side effects associated with their use, and many individuals do not respond to any medications. Neuropathic pain drugs with novel mechanisms of action are being sought as an alternative; however, the only successful FDA-approved drugs, which target calcium channels, have serious limitations to their widespread use. Neurotensin (NT) and its fully active fragment NT(8- 13) have been shown to possess dramatic activity against neuropathic pain when dosed centrally; however, activity is not seen with systemic administration. Halimed Pharmaceuticals has engineered NT(8-13) derivatives that exhibit potent analgesic activity when dosed IV (and, at high concentrations, orally). The compounds are NT-receptor agonists, a novel mechanism of analgesia, thus they may not have the limitations of currently approved medications. We hypothesize that engineered NT(8-13) derivatives can be developed as novel neuropathic pain medications, the foundation of which will be provided by the completion of two Specific Aims in this Phase I application. In Specific Aim 1, 14 highly potent NT(8-13) derivatives will be fully evaluated in the standard Chung model of neuropathic pain with both IV and oral administration. In vitro potency/receptor binding with the two cloned and expressed rat and human NT receptors (NTRs) also will be determined to establish whether there is a correlation with the in vivo results; this would potentially suggest a mechanism of action. The overall stability (degradation t1/2s) of each compound will be determined in simulated intestinal and gastric fluid, plasma, and homogenized brain preparations. This will enable evaluation of whether the relative receptor binding potency and/or one or a combination of half-lives in the different environments is predictive of overall analgesic activity. The three most potent compounds will be advanced into Specific Aim 2, in which their pharmacokinetic/pharmacodynamics properties will be fully characterized. The PK/PD data are crucial for developing the study designs for preclinical toxicity and safety evaluations in animals prediction of effective human dose, and ultimately design of clinical trials. Characterization of three compounds through this Aim will enable flexibility as the program moves forward. Completion of this Aim will provide the foundation needed for preparation of a Phase II application to develop the lead through preclinical studies (synthesis, toxicity, etc.) and IND preparation and submission. This Phase I effort will be performed at Halimed Pharmaceuticals and in collaboration with the PI's long-term collaborator, Dr. Craig Beeson, at the Medical University of South Carolina.