Development of Pathology-activated Drugs for Treatment of Neuropathic Pain

开发用于治疗神经性疼痛的病理激活药物

基本信息

批准号：
10574306
负责人：
Andrew Abell
金额：
$ 240.81万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10574306
关键词：
Adverse effects Adverse event Analgesics Anti-Inflammatory Agents Antioxidants Behavior Benchmarking Benign Binding Proteins Biochemical Biochemical Pathway Biological Biological Assay Canis familiaris Cardiovascular system Chemicals Data Development Diabetic Neuropathies Dose Drug Kinetics FDA approved Fumarates G-Protein-Coupled Receptors Heart Hydrogen Peroxide Immune Immunosuppression In Vitro Inflammation Mediators Ion Channel Kidney Lead Libraries Maximum Tolerated Dose Mediating Mediator of activation protein Metabolic Metabolic Pathway Mission Modeling National Institute of Neurological Disorders and Stroke Neuraxis Nitrogen Oxygen Pain Pathology Pathway interactions Peripheral Nervous System Diseases Peroxonitrite Pharmaceutical Preparations Pharmacology Study Pharmacotherapy Phase Phase I Clinical Trials Plasma Positioning Attribute Positron-Emission Tomography Pre-Clinical Model Preclinical Drug Development Prodrugs Program Development Property Protein Isoforms Public Health Rattus Reflex action Reporter Research Research Project Grants Resources Risk Rodent Rodent Model Route Safety Series Site Structure System Therapeutic Therapeutic Agents Therapeutic Index Time Tissues Toxic effect Type 2 diabetic base chemical reaction chemical stability chronic pain chronic pain management compound 30 design drug development drug reinforcement gastrointestinal imaging biomarker improved in vitro Assay in vivo in vivo Model innovation iterative design lead optimization manufacturing scale-up multidisciplinary multiple sclerosis treatment non-opioid analgesic nuclear factor-erythroid 2 pain behavior pain model painful neuropathy pre-clinical programs respiratory risk benefit ratio side effect small molecule standard of care targeted biomarker targeted treatment therapeutic target treatment response

项目摘要

Current therapeutics for neuropathic pain are poorly efficacious. One likely reason is that current therapies target only a single biochemical mechanism or pathway while chronic pain is a multi-mechanism problem. Fumarates, such as monomethyl fumarate (MMF), are uniquely positioned to treat the multi-mechanism problem of pain due to their combined antioxidant and anti-inflammatory profile. However, the risk-benefit ratio of fumarates is unacceptable for treatment of chronic pain, given their poor gastrointestinal tolerability and indiscriminate immune interference. This research project proposes to build on the documented analgesic efficacy of fumarates by designing new MMF prodrugs that have improved tolerability through design of non-reactive prodrugs. To reduce systemic immune interference, prodrugs will further be designed to preferentially release MMF, the active metabolite, only where ROS/RNS are overproduced in the pain neuraxis. The overall objective is to develop a 1,2-dicarbonyl prodrug that preferentially releases MMF at sites of pathology to alleviate neuropathic pain, while reducing adverse effects caused by systemic distribution of fumarates. Preliminary data indicate that the antioxidant master regulator nuclear factor erythroid 2-related factor 2 (NRF2) is a major therapeutic target. Using validated NRF2 activators and standard of care therapeutics as comparators, the UG3 specific aims are: 1) Complete initial characterization of the lead 1,2-dicarbonyl MMF prodrug; 2) Optimize lead compound, and design and evaluate backup 1,2-dicarbonyl MMF prodrugs; and 3) Characterize safety, validate analgesic efficacy of lead and backup 1,2-dicarbonyl MMF prodrugs. The exploratory milestones will identify a lead and backup molecules. These compounds will be advanced through IND-enabling studies under the following UH3 phase specific aims: 4) Extensive PK/PD characterization of candidates; 5) demonstrate in vivo efficacy in established rodent models of neuropathic pain; 6) Dose range finding to establish maximal tolerated dose (MTD) and cardiovascular, respiratory and gastrointestinal safety and toxicity studies; and 7) establish a Lead Development Team to finalize an IND application. BPN resources will be engaged for CMC manufacture and scale up, and development of a phase 1 clinical trial plan. Successful completion of this project will have major impact by first-in-class target activated delivery of a non-opioid therapeutic agent (MMF) to localized regions of pain pathology. Site-specific release of MMF will reduce its adverse effects, eliminating the final hurdles to MMF- based treatment of neuropathic pain.

目前针对神经性疼痛的治疗方法效果不佳。一个可能的原因是，当前的疗法仅针对单一生化机制或途径，而慢性疼痛是一个多机制问题。富马酸盐，例如富马酸单甲酯 (MMF)，由于其结合的抗氧化和抗炎特性，在治疗疼痛的多机制问题方面具有独特的优势。然而，由于富马酸盐的胃肠耐受性差和无差别的免疫干扰，富马酸盐治疗慢性疼痛的风险效益比是不可接受的。该研究项目拟在已有的富马酸盐镇痛功效的基础上，设计新的 MMF 前药，通过设计非反应性前药来提高耐受性。为了减少全身免疫干扰，前药将进一步设计为仅在疼痛神经轴中过量产生 ROS/RNS 时优先释放 MMF（活性代谢物）。总体目标是开发一种 1,2-二羰基前药，可优先在病理部位释放 MMF 以减轻神经性疼痛，同时减少富马酸盐全身分布引起的不良反应。初步数据表明，抗氧化剂主调节因子核因子红细胞 2 相关因子 2 (NRF2) 是一个主要的治疗靶点。使用经过验证的 NRF2 激活剂和护理治疗标准作为比较，UG3 的具体目标是： 1) 完成先导 1,2-二羰基 MMF 前药的初步表征； 2) 优化先导化合物，并设计和评价备用1,2-二羰基MMF前药； 3) 表征安全性，验证先导和备用 1,2-二羰基 MMF 前药的镇痛功效。探索性里程碑将确定主导分子和备用分子。这些化合物将通过以下 UH3 阶段特定目标的 IND 支持研究来推进：4) 候选药物的广泛 PK/PD 表征； 5) 在已建立的神经性疼痛啮齿动物模型中证明体内功效； 6) 确定剂量范围以建立最大耐受剂量（MTD）以及心血管、呼吸和胃肠道安全性和毒性研究； 7) 建立一个牵头开发团队来完成 IND 申请。 BPN 资源将用于 CMC 生产和扩大规模，以及制定一期临床试验计划。该项目的成功完成将对向局部疼痛病理区域首次靶向激活非阿片类治疗剂（MMF）输送产生重大影响。 MMF 的位点特异性释放将减少其副作用，消除基于 MMF 治疗神经性疼痛的最终障碍。