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: 10408164
• 负责人: Graham Beaton
• 金额: $ 99.07万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408164
• 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; Persons; Phase; Physiological; Process; Production; Rattus; Recommendation; Risk Factors; Rodent; Safety; Sampling; Spinal; Spinal Cord; Spinal Cord Diseases; Streptozocin; Synapses; Synaptophysin; Testing; Time; Tissues; Toxic effect; Translating; Type 2 diabetic; Universities; antagonist; 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 糖尿病神经病变（DPN）是一个主要的未得到满足的健康问题，估计3300万人中有一半以上 在美国，1型或2型糖尿病患者会出现神经病变1。没有FDA批准的疾病修饰 用于预防或减缓糖尿病性神经病变进展的治疗， 血糖控制2和目前的治疗仅限于管理 神经病变如疼痛。越来越多的人认识到，糖尿病也会损害脊髓， 糖尿病（脊髓病）和脑（脑病），因此糖尿病被认为是 发展认知功能障碍和阿尔茨海默病14.因此，防止或逆转 糖尿病期间的外周神经和/或CNS损伤作为独立的药剂或用于治疗是令人感兴趣的。 使用对症治疗。Epigen在发现和开发 用于治疗纤维化疾病的新型溶血磷脂酸受体1（LPAR 1）拮抗剂。并行 糖尿病肾病研究的数据表明，在Epigen发现的铅化合物 也有益于糖尿病神经病变的神经损伤终点和模型中认知下降的标志物。 该提案基于这些数据来确定是否可以开发一种这样的先导化合物EPGN 2154， 治疗糖尿病神经病变。本次直接进入II期申请的目的是进行详细的临床前疗效研究 EPGN 2154在大鼠DPN模型中的剂量，沿着筛选安全性以允许提名开发候选物。 在加州圣地亚哥大学进行测试之前，将在Epigen制备和表征化合物 （UCSD）在奈杰尔卡尔卡特博士的指导下。卡尔卡特博士的实验室将建立并维持 糖尿病啮齿动物，用Epigen提供的测试试剂治疗它们，并测量它们的生理、行为和 在整个研究期间的不同时间，外周和中枢神经病变的结构指数。经研究 完成组织将被解剖和处理，用于组织学和生化评价，以支持 行为测量Epigen将进行额外的铅分析，以支持EPGN 2154的候选资格。药物 还将对分布进行评价，以支持机理研究。复合分析将包括安全性 EPGN 2154的评估。这些研究将支持将EPGN 2154推进为IND使能研究 作为进入DPN临床试验的前奏