Novel NMDA Receptor Antagonists for Beta Cell Rescue

 描述(申请人提供)：新型NMDA受体拮抗剂用于贝塔细胞救援摘要2型糖尿病(T2 DM)正迅速成为美国最常见的慢性疾病，有超过7%的成年人受到影响，每年新增病例150万例。从根本上说，T2 DM涉及β细胞功能障碍和血糖水平控制不佳，导致高血糖。伴随着胰岛素分泌受损的是β细胞质量的减少，β细胞的凋亡率增加，以及剩余细胞的功能能力降低。疾病修正治疗不仅会促进胰岛素的分泌，还会减少β细胞的凋亡和促进其增殖。最近来自动物模型和人类第二阶段临床研究的数据表明，NMDA受体(NMDAR)抑制胰岛素释放并促进β细胞死亡，NMDAR拮抗剂起到胰岛素促分泌剂的作用，可以增加β细胞质量。虽然需要进一步的机制研究才能完全了解NMDARs在β细胞中的功能，但NMDARs可能作为胰岛负反馈循环的一部分，以确保胰岛素在高血糖浓度下不会过度释放。大剂量和长期暴露于NMDAR拮抗剂缺乏极端的降血糖作用，这表明这种治疗不太可能导致威胁生命的低血糖，就像磺脲类药物治疗那样。长期使用高剂量NMDAR拮抗剂与低剂量NMDAR拮抗剂相比，在糖尿病小鼠中观察到更大的胰岛细胞团，这也表明抑制NMDAR可以维持糖尿病患者的β细胞数量。这些数据表明，NMDAR拮抗剂可能有助于减少甚至逆转人类糖尿病的进展。美金刚是一种氨基金刚烷，它选择性地抑制异常活跃的NMDAR通道，同时保留正常的活动和生理神经元功能。美金刚被批准用于治疗中到重度阿尔茨海默病已有10多年的历史。病理上的N-甲基-D-天冬氨酸受体活性被特定半胱氨酸残基的S亚硝化进一步下调。利用这些见解，PRI开发了一系列专有的双功能拮抗剂，称为亚硝胺，它们不仅优先与开放通道状态结合，而且利用记忆药效基团作为归巢基序，选择性地将NO靶向NMDAR上的第二个调制位点。在这项第一阶段的研究中，我们将评估我们的先导硝基美金胺YQW-036在体外和T2 DM动物模型中的活性。这些里程碑的成功实现将为T2 DM提供一种专利的一流疾病修改药物。

 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.