Selection of a lead LPAR1 antagonist for treatment of diabetic neuropathy

选择用于治疗糖尿病神经病变的主要 LPAR1 拮抗剂

• 批准号: 10259568
• 负责人: Graham Beaton
• 金额: $ 103.58万
• 依托单位: EPIGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-20 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259568
• 关键词: ADME Study; Alzheimer' s Disease; Analgesics; Behavioral; Biochemical; Biological Assay; Brain; California; Clinical Trials; Cytochrome P450; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic Neuropathies; Disease; Encephalopathies; Enzyme Inhibition; Evaluation; Exposure to; FDA approved; Functional disorder; Goals; Grant; Health; High Fat Diet; Hippocampus (Brain); Histologic; Impact evaluation; Impaired cognition; Insulin-Dependent Diabetes Mellitus; Laboratories; Lead; Lysophosphatidic Acid Receptors; Measures; Metabolic syndrome; Metabolism; Modeling; Morphology; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Pain; Pathogenicity; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Phase; Physiological; Process; Production; Rattus; Recommendation; Risk Factors; Rodent; Safety; Sampling; Spinal; Spinal Cord; Spinal Cord Diseases; Streptozocin; Structure; Synapses; Synaptophysin; Testing; Time; Tissues; Toxic effect; Translating; Type 2 diabetic; Universities; behavior measurement; behavioral study; diabetic; diabetic rat; drebrins; drug distribution; effective therapy; epigen; glycemic control; indexing; interest; nerve injury; nonhuman primate; novel; novel therapeutics; preclinical efficacy; preclinical study; prevent; safety assessment; safety study; scale up; screening; small molecule; symptom treatment; therapeutic candidate

PROJECT SUMMARY Diabetic neuropathy (DPN) is a major unmet health concern where over half of the estimated 33 million people in the US with type 1 or type 2 diabetes will develop neuropathy1. There is no FDA-approved disease modifying treatment for preventing or slowing progression of diabetic neuropathy other than a recommendation to maintain glycemic control2 and current treatments are restricted to management of the symptomatic consequences of neuropathy such as pain. It is becoming increasingly appreciated that diabetes also injures both the spinal cord (myelopathy) and brain (encephalopathy) such that diabetes is recognized as a prominent risk factor for developing cognitive dysfunction and Alzheimer’s disease14. Accordingly, agents that prevent or reverse peripheral nerve and/or CNS insults during diabetes are of interest either as standalone agents or for adjunctive use with symptomatic treatments. Epigen has developed expertise around the discovery and development of novel lysophosphatidic acid receptor type 1 (LPAR1) antagonists for the treatment of fibrotic disease. In parallel to the study of diabetic nephropathy data was obtained to suggest that lead compounds discovered at Epigen also benefit endpoints of diabetic neuropathy for both nerve injury and markers for cognitive decline in models. This proposal builds on these data to determine if one such lead compound, EPGN2154, may be developed to treat diabetic neuropathy. The goal of this direct to phase 2 application is to conduct detailed pre-clinical efficacy of EPGN2154 in rat DPN models, along with screening safety to allow nomination of a development candidate. Compounds will be prepared and characterized at Epigen prior to testing at University of California San Diego (UCSD) under the guidance of Dr. Nigel Calcutt. Dr. Calcutt’s laboratory will establish and maintain colonies of diabetic rodents, treat them with test agents provided by Epigen and measure physiological, behavioral and structural indices of peripheral and central neuropathy at assorted times throughout the study. Upon study completion tissue will be dissected and processed for histological and biochemical evaluation to support behavioral measurements. Epigen will conduct additional lead profiling to support candidacy of EPGN2154. Drug distribution will also be evaluated to support mechanistic studies. Compound profiling will include a safety assessment of EPGN2154. These studies will support the advancement of EPGN2154 to IND enabling studies as a prelude to entry into clinical trials for DPN.

项目摘要 糖尿病神经病（DPN）是一个主要的未得到健康关注，其中估计有3300万人中有一半以上 在美国，具有1型或2型糖尿病的糖尿病将发展神经病。没有FDA批准的疾病修饰 预防或放缓糖尿病神经病进展的治疗 血糖控制2和当前治疗仅限于管理的症状后果 神经病，例如疼痛。越来越多的糖尿病也受到脊髓的伤害 （脊髓病）和大脑（脑病），使糖尿病被认为是重要的危险因素 发展认知功能障碍和阿尔茨海默氏病14。根据以下内容，预防或反向的代理 糖尿病期间的外周神经和/或CNS侮辱是独立的，或者是辅助的 与症状治疗一起使用。 Epgen围绕发现和发展的专业知识 新型的溶血磷脂酸受体1型（LPAR1）拮抗剂用于治疗纤维化疾病。并联 获得了糖尿病性肾病数据的研究，以表明在表格上发现的铅化合物 还使糖尿病神经病的终点造成神经损伤和模型认知能力下降的标记。 该建议基于这些数据，以确定是否可以开发出一种这样的铅化合物EPGN2154 治疗糖尿病神经病。直接到第2阶段应用的目的是进行详细的临床前效率 大鼠DPN模型中的EPGN2154，以及筛查安全性，以提名开发候选者。 在加利福尼亚大学圣地亚哥分校测试之前，将在Epigen准备和特征化合物 （UCSD）在Nigel Calcutt博士的指导下。加尔各答博士的实验室将建立并维护 糖尿病啮齿动物，用由表格提供的测试剂对其进行处理，并测量生理，行为和 在整个研究中，各种时间的周围和中枢神经病的结构指标。学习 将解剖和处理完成组织，以进行组织学和生化评估以支持 行为测量。 Epigen将进行额外的铅分析，以支持EPGN2154的候选。药品 还将评估分布以支持机械研究。复合分析将包括安全 评估EPGN2154。这些研究将支持EPGN2154的进步以促进研究 作为进入DPN临床试验的前奏。