Novel NMDA Receptor Antagonists for Beta Cell Rescue

用于拯救 Beta 细胞的新型 NMDA 受体拮抗剂

• 批准号: 9047082
• 负责人: JAMES W LARRICK
• 金额: $ 22.46万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2017-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047082
• 关键词: Achievement; Activities of Daily Living; Adult; Affect; Aftercare; Agonist; Alzheimer' s Disease; Animal Model; Apoptosis; Beta Cell; Binding; Blood Glucose; Cardiovascular system; Cell Death; Cells; Chronic Disease; Clinical Research; Cysteine; Data; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Dose; Drug Kinetics; Ensure; Exposure to; Eye diseases; Feedback; Functional disorder; Genetic; Glucose; Homing; Human; Hyperglycemia; Hypoglycemia; In Vitro; Incidence; Insulin; Islet Cell; Islets of Langerhans; Kidney; Laboratories; Lead; Life; Maintenance; Measures; Memantine; Methods; Modeling; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pharmaceutical Preparations; Phase; Physiological; Population; Preparation; Rodent Model; Series; Site; Structure; Structure of beta Cell of islet; Sulfonylurea Compounds; Therapeutic; Time; Toxicology; Work; abstracting; base; disorder risk; exenatide; glucose tolerance; improved; in vitro activity; insight; insulin secretagogues; insulin secretion; novel; patch clamp; pharmacophore; phase 1 study; public health relevance; receptor

 DESCRIPTION (provided by applicant): Novel NMDA Receptor Antagonists for Beta Cell Rescue Abstract Type 2 diabetes mellitus (T2DM) is rapidly becoming the most common chronic disease in the US, with more than 7% of the adult population affected and 1.5 million new cases per year. Fundamentally, T2DM involves beta cell dysfunction and poor control of blood glucose levels, resulting in hyperglycemia. Impaired insulin secretion is accompanied by a decrease in beta cell mass, an increase in apoptosis of beta cells, and a reduced functional capacity of the remaining cells. A disease-modifying treatment would not only promote insulin secretion, but also reduce apoptosis and increase proliferation of beta cells. Recent data from animal models and Phase 2 clinical studies in humans suggest that NMDA receptors (NMDAR) inhibit insulin release and promote beta cell death and that NMDAR antagonists act as insulin secretagogues and can increase beta cell mass. Although further mechanistic studies are required to fully understand the function of NMDARs in beta cells, NMDARs may act as part of a negative feedback loop in pancreatic islets to ensure that insulin is not released in an excessive manner at high blood glucose concentrations. The lack of extreme blood glucose lowering effects with high-dose and long-term exposure to NMDAR antagonists suggests that such treatment is unlikely to lead to life-threatening hypoglycemia such as is seen with sulfonylurea treatment. The larger islet cell mass observed in diabetic mice upon long-term treatment with a high dose versus a low dose of NMDAR antagonists also indicates that inhibition of NMDARs could maintain the number of beta cells in diabetes. These data suggest that NMDAR antagonists may be useful to reduce or even reverse progression of human diabetes. Memantine, an aminoadamantane, selectively inhibits abnormally active NMDAR channels, while preserving normal activity and physiological neuronal function. Memantine has been approved for the treatment of moderate-to-severe Alzheimer's disease for over 10 years. Pathological NMDA receptor activity is further down-regulated by S-nitrosylation of specific cysteine residues. Taking advantage of these insights, PRI has developed a proprietary series of bifunctional antagonists, called nitromemantines, that not only preferentially bind to the open-channel state but also selectively target NO to a second modulatory site on the NMDAR using the memantine pharmacophore as a homing motif. During this Phase I study, we will evaluate our lead nitromemantine, YQW-036, for its activity in vitro and in an animal model of T2DM. Successful achievement of these milestones will provide a proprietary first-in-class disease-modifying drug for T2DM.

 描述（由申请人提供）：用于拯救 Beta 细胞的新型 NMDA 受体拮抗剂 摘要 2 型糖尿病 (T2DM) 正在迅速成为美国最常见的慢性疾病，超过 7% 的成年人口受到影响，新增病例达 150 万例从根本上来说，T2DM 涉及 β 细胞功能障碍和血糖水平控制不良，导致高血糖并伴有胰岛素分泌下降。 β细胞质量、β细胞凋亡增加以及其余细胞功能能力降低，疾病缓解治疗不仅会促进胰岛素分泌，而且会减少细胞凋亡并增加β细胞增殖。人体 2 期临床研究表明，NMDA 受体 (NMDAR) 抑制胰岛素释放并促进 β 细胞死亡，而 NMDAR 拮抗剂可充当胰岛素促分泌剂，并可增加 β 细胞质量，但需要进一步的机制研究来充分了解其功能。 β细胞中的NMDAR可能作为胰岛负反馈回路的一部分，以确保胰岛素在高血液浓度下不会过度释放。大剂量和长期的情况下，不会产生极端的血糖降低作用。暴露于 NMDAR 拮抗剂表明，这种治疗不太可能导致危及生命的低血糖，如磺酰脲类药物长期治疗后在糖尿病小鼠中观察到的较大胰岛细胞团。高剂量与低剂量的 NMDAR 拮抗剂还表明，抑制 NMDAR 可以维持糖尿病中的 β 细胞数量。这些数据表明，NMDAR 拮抗剂可能有助于选择性地减少甚至逆转人类糖尿病的进展。抑制异常活跃的 NMDAR 通道，同时保留正常的活性和生理神经元功能 美金刚已被批准用于治疗中度至重度阿尔茨海默病。 NMDA 受体活性通过特定半胱氨酸残基的 S-亚硝基化进一步下调，PRI 利用这些见解开发了一系列专有的双功能拮抗剂，称为硝基美金刚，它不仅优先与开放通道状态结合，而且还可以与开放通道状态结合。还使用美金刚药效团作为归巢基序选择性地将 NO 靶向 NMDAR 上的第二个调节位点。在这一阶段的研究中，我们将评估我们的先导硝基美金刚， YQW-036 因其在体外和 T2DM 动物模型中的活性而成功实现这些里程碑将为 T2DM 提供一种专有的一流疾病缓解药物。