Engineered Neurotensin Fragments Targeting Neuropathic Pain

描述(由申请人提供)：神经病理性疼痛管理是一个主要的未满足的临床需求。传统使用的药物，包括阿片类药物和非阿片类药物(主要是非类固醇类药物)，与其使用有关的主要副作用，许多人对任何药物都没有反应。人们正在寻找具有新作用机制的神经性止痛药作为替代药物；然而，FDA批准的唯一成功的针对钙通道的药物，在广泛使用方面存在严重限制。神经降压素(NT)及其完全活性片段NT(8-13)已被证明在中枢给药时具有显著的抗神经病理性疼痛的活性；然而，全身给药没有看到这种活性。Halimed制药公司已经设计出NT(8-13)衍生物，在静脉注射时(以及在高浓度下，口服)显示出强大的止痛活性。这些化合物是NT受体激动剂，这是一种新的止痛机制，因此它们可能没有目前批准的药物的局限性。我们假设，工程化的NT(8-13)衍生物可以被开发为新的神经病理性止痛药，其基础将通过完成这一第一阶段应用中的两个特定目标而提供。在具体目标1中，14个高效力的NT(8-13)衍生物将在静脉注射和口服给药的标准Chung神经病理性疼痛模型中进行全面评估。体外效力/受体与两个克隆和表达的大鼠和人NT受体(NTR)的结合也将被确定是否与体内结果相关；这可能表明 作用机制。每种化合物的总体稳定性(降解T1/2s)将在模拟的肠液和胃液、血浆和匀浆的脑制剂中确定。这将能够评估不同环境中的相对受体结合效力和/或半衰期的一个或组合是否预测总体止痛剂 活动。三种最有效的化合物将被推进到特定目标2，其中将充分描述它们的药代动力学/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估的研究设计、预测人体有效剂量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在推进过程中具有灵活性。完成这一目标将为通过临床前研究(合成、毒性等)开发铅的第二阶段申请准备所需的基础。以及IND的编制和提交。这项第一阶段的工作将在Halimed制药公司进行，并与PI的长期合作伙伴南卡罗来纳医科大学的Craig Beeson博士合作进行。

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.