Engineered Neurotensin Fragments Targeting Neuropathic Pain

针对神经性疼痛的工程神经降压素片段

• 批准号: 8645232
• 负责人: Thomas A. Dix
• 金额: $ 32.43万
• 依托单位: JT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2016-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645232
• 关键词: Absence of pain sensation; Acute; Acute Pain; Address; Adverse effects; Affect; Aging; Agonist; Amino Acids; Analgesics; Animal Model; Animals; Antipsychotic Agents; Binding; Biological; Biological Assay; Biological Availability; Blood; Blood - brain barrier anatomy; Body Fluids; Brain; Calcium Channel; Chronic; Chung model; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Data; Data Set; Development; Dose; Drug Kinetics; Engineering; Environment; Evaluation; Exhibits; FDA approved; Foundations; Future; Human; In Vitro; Individual; Intestines; Investigation; Lead; Liquid substance; Malignant Neoplasms; Measures; Medical; Modeling; Modification; Morphine; N-terminal; Neuropathy; Neurotensin; Neurotensin Receptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Oral; Oral Administration; Pain; Pain management; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Physiological; Plasma; Preparation; Property; Rattus; Relative (related person); Research Design; Series; Simulate; Site; South Carolina; Stomach; Technology; Therapeutic; Time; Toxic effect; Universities; analog; arginyllysine; base; drug development; flexibility; improved; in vivo; novel; novel therapeutics; painful neuropathy; pre-clinical; preclinical safety; preclinical study; preclinical toxicity; programs; public health relevance; receptor; receptor binding; response

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.

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（主要是非甾体抗炎药），具有与其使用相关的严重副作用，并且许多人对任何药物都没有反应。人们正在寻找具有新颖作用机制的神经病理性疼痛药物作为替代方案；然而，FDA 批准的唯一成功的针对钙通道的药物，其广泛使用受到严重限制。神经降压素 (NT) 及其完全活性片段 NT(8-13) 已被证明在集中给药时具有显着的抗神经性疼痛活性；然而，全身给药并未观察到活性。 Halimed Pharmaceuticals 设计了 ​​NT(8-13) 衍生物，在静脉注射（以及高浓度口服）时表现出有效的镇痛活性。这些化合物是 NT 受体激动剂，是一种新的镇痛机制，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) 衍生物可以开发为新型神经病理性疼痛药物，其基础将通过完成该 I 期申请中的两个特定目标来提供。在具体目标 1 中，将在神经性疼痛的标准 Chung 模型中通过静脉注射和口服给药对 14 种高效 NT(8-13) 衍生物进行全面评估。还将确定与两个克隆和表达的大鼠和人类 NT 受体 (NTR) 的体外效力/受体结合，以确定是否与体内结果存在相关性；这可能会建议 作用机制。每种化合物的总体稳定性（降解 t1/2s）将在模拟肠液和胃液、血浆和均质脑制剂中测定。这将能够评估不同环境中的相对受体结合效力和/或半衰期之一或组合是否可以预测总体镇痛作用 活动。三种最有效的化合物将进入特定目标 2，其中它们的药代动力学/药效学特性将得到充分表征。 PK/PD 数据对于开发动物临床前毒性和安全性评估、预测人体有效剂量的研究设计以及最终设计临床试验至关重要。通过该目标对三种化合物进行表征将为项目的推进提供灵活性。该目标的完成将为准备 II 期申请提供所需的基础，以通过临床前研究（合成、毒性等）以及 IND 准备和提交来开发先导药物。第一阶段的工作将在 Halimed Pharmaceuticals 进行，并与 PI 的长期合作者、南卡罗来纳医科大学的 Craig Beeson 博士合作。