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（由适用提供）：β细胞救援摘要2糖尿病（T2DM）的新型NMDA受体拮抗剂（T2DM）迅速成为美国最常见的慢性疾病，其中7％以上受影响的成人人群，每年150万例新病例。从根本上讲，T2DM涉及β细胞功能障碍和对血糖水平的控制不佳，导致高血糖。胰岛素分泌受损是动物模型的最新数据，人类的2阶段临床研究表明，NMDA受体（NMDAR）抑制胰岛素释放并促进β细胞死亡，并且NMDAR拮抗剂充当胰岛素促分泌物，并且可以增加β细胞量。尽管需要进一步的机械研究以充分了解NMDAR在β细胞中的功能，但NMDAR可能是胰岛中负反馈回路的一部分，以确保在高血糖浓度下不会以过量的方式释放胰岛素。缺乏高剂量和长期暴露于NMDAR拮抗剂的极端血糖降低作用表明，这种治疗不太可能导致威胁生命的低血糖症，例如通过磺酰脲治疗可以看出。长期用高剂量与低剂量的NMDAR拮抗剂长期治疗后，在糖尿病小鼠中观察到的较大的胰岛细胞量也表明，NMDAR的抑制可以维持糖尿病中β细胞的数量。这些数据表明，NMDAR拮抗剂可能有助于减少人类糖尿病的进展甚至逆转。美金刚（Memantine）是一种氨基烷坦烷，有选择地抑制绝对活性的NMDAR通道，同时保留正常活性和物理神经元功能。纪念碑已被批准用于治疗中度至严重的阿尔茨海默氏病，已有10多年的历史了。病理NMDA受体活性通过特异性半胱氨酸保留的S-硝基化进一步下调。利用这些洞察力，PRI开发了一系列专有的双功能拮抗剂，称为硝基绝素，这些拮抗剂不仅优先与开放通道状态结合，而且还将使用Memantine Pharmacophore作为HOMING HOHING MOTIF的NMDAR上的第二个调节位点选择性地靶向NMDAR上的第二个调节位点。在此阶段I研究中，我们将评估其在体外活性和T2DM动物模型中的氮含量YQW-036。这些里程碑的成功实现将为T2DM提供专有的一类疾病改良药物。