ORALLY ACTIVE INHIBITOR OF POLY (ADP) RIBOSE SYNTETHASE

口服活性聚 (ADP) 核糖合成酶抑制剂

• 批准号: 6071709
• 负责人: JON G MABLEY
• 金额: $ 12.55万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6071709
• 关键词: NOD mouse; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; hypoglycemic agents; immunocytochemistry; insulin dependent diabetes mellitus; oral administration; pancreatic islet disorder; pancreatic islets; pentosyltransferase; peroxynitrites; pharmacokinetics

The cellular and molecular mechanisms of free radical-related pancreatic islet cell destruction are incompletely understood. Pharmacological modulation of this islet cell death may provide novel avenues for the experimental therapy of diabetes. Recent studies in isolated islet cells, and other cell types demonstrate that peroxynitrite and hydrogen peroxide, potent oxidants produced during immune-cell mediated islet cell attack, trigger an intracellular cascade culminating in cellular energy failure. DNA strand-breakage triggered by hydrogen peroxide and peroxynitrite is recognized by a specific domain of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). This results in the activation of PARS which initiates an energy consuming inefficient repair cycle, with resultant depletion of dinucleotide pools, slowing the rate of glycolysis and mitrochondrial respiration, reducing ATP synthesis. Thus, PARS acts as a terminal mediator of cellular energetic collapse leading to cellular necrosis. Our preliminary data show that pharmacological inhibition of PARS with a novel, potent inhibitor of PARS reduces the development of hyperglycemia and islet cell destruction in a rat model of streptozotocin- induced diabetes. The inhibitor was effective in the oral treatment regimen. In addition to the data with pharmacological inhibitors, data from our group, and also from two other group, and also from two other groups of investigators demonstrate that PARS deficient (knockout) mice are resistant against streptozotocin-induced diabetes. Because of the streptozotocin-model is not fully predictable for the human situation, the first aim of the current protocol is aimed at investigating the effect of oral treatment with PARS inhibitor on the development of spontaneous autoimmune diabetes (NOD mice). The second aim of the proposed studies is to perform standard preclinical studies to begin to characterize the toxicity and pharmacodynamics of orally administered PARS inhibitor. The current proposal will provide (1) novel mechanistic information on the mechanism of autoimmune diabetes, and (2) will result in data which will help our company in making a strategic decision for the preclinical development of a novel, potent, orally active PARS inhibitors. PROPOSED COMMERCIAL APPLICATION: To market for a safe and effective therapy for autoimmune diabetes is estimated at > $1 billion in the US per annum.

自由基相关的胰岛细胞破坏的细胞和分子机制还不完全清楚。这种胰岛细胞死亡的药理学调节可能为糖尿病的实验治疗提供新的途径。最近在分离的胰岛细胞和其他细胞类型中的研究表明，过氧亚硝酸盐和过氧化氢，在免疫细胞介导的胰岛细胞攻击期间产生的有效氧化剂，触发细胞内级联反应，最终导致细胞能量衰竭。由过氧化氢和过氧亚硝酸盐引发的DNA链断裂由核酶聚（ADP-核糖）合成酶（PARS）的特定结构域识别。这导致PARS的激活，其启动能量消耗低效的修复循环，导致二核苷酸池的耗尽，减缓糖酵解和线粒体呼吸的速率，减少ATP合成。因此，PARS充当导致细胞坏死的细胞能量崩溃的终末介质。我们的初步数据表明，在链脲佐菌素诱导的糖尿病大鼠模型中，用新型有效的PARS抑制剂药理学抑制PARS可减少高血糖症的发生和胰岛细胞的破坏。该抑制剂在口服治疗方案中有效。除了药理学抑制剂的数据之外，我们小组、另外两个小组以及另外两个研究小组的数据表明，PARS缺陷（基因敲除）小鼠对链脲佐菌素诱导的糖尿病具有抵抗力。由于链脲佐菌素模型不能完全预测人类的情况，本方案的第一个目的是研究口服PARS抑制剂对自发性自身免疫性糖尿病（NOD小鼠）发展的影响。拟定研究的第二个目的是进行标准临床前研究，以开始表征口服PARS抑制剂的毒性和药效学。 目前的提案将提供（1）关于自身免疫性糖尿病机制的新机制信息，以及（2）将产生有助于我们公司为临床前开发新型，强效，口服活性PARS抑制剂做出战略决策的数据。拟议的商业应用：在美国，用于自身免疫性糖尿病的安全有效疗法的市场估计每年超过10亿美元。