Poly(ADP-ribose) synthetase inhibition and diabetes

聚（ADP-核糖）合成酶抑制与糖尿病

• 批准号: 6582906
• 负责人: CSABA SZABO
• 金额: $ 19.98万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6582906
• 关键词: cytoprotection; drug design /synthesis /production; drug screening /evaluation; endocrine pharmacology; enzyme activity; enzyme inhibitors; flow cytometry; guanosine monophosphate; insulin dependent diabetes mellitus; laboratory mouse; myocardium disorder; oxidative stress; pancreatic islets; pentosyltransferase; pharmacokinetics

DESCRIPTION (provided by applicant): The current application represents the Phase I component of a Fast-Track SBIR Grant by Inotek Corporation, proposing to establish a proof-of-concept of the involvement of poly (ADP-ribose) polymerase (PARP) activation in the pathogenesis of Type I diabetes mellitus and its complications, and to test the effect of pharmacological inhibition of PARP in murine models of diabetes and its complications. As preliminary data the investigators present evidence in cultured islet cells, showing that PARP activation plays a key role in the development of oxidant-mediated islet cell injury and in diabetic cardiovascular complications. The investigators now have synthesized a potent PARP inhibitor as a lead developmental candidate agent for the experimental therapy of beta cell destruction associated with autoimmune diabetes as well as its complications. The central aim of Phase I component is to perform proof-of-concept in vivo studies in diabetic rodents. If these studies confirm that Inotek's PARP inhibitor is remarkably effective in streptozotocin and NOD models of diabetes, and protects against diabetic complications, a Phase II component will be triggered, which will focus on formal pre-clinical safety testing. In the Phase II component of the current SBIR application, the investigators propose to perform pre-clinical safety studies with GLP quality material. A GMP quality synthesis of the compound will be developed and the compound formulated as an oral drug. In addition, the investigators propose formal safety studies and, for the second year of the project an accelerated carcinogenicity trial in the P53 mice. These latter studies are essential for the future introduction of a potent PARP inhibitor into the clinical management of diabetes mellitus. Taken together, the investigators request funds from the NIH to develop a potent, orally bioavailable PARS inhibitor, which is expected to be effective in reducing the incidence of type I diabetes, and in attenuating hyperglycemia-induced vascular complications (in established Type I and Type II diabetes).

描述（由申请人提供）：本申请代表了Inotek Corporation的快速通道SBIR资助的I期部分，拟建立聚（ADP-核糖）聚合酶（PARP）激活参与I型糖尿病及其并发症发病机制的概念验证，并在糖尿病及其并发症小鼠模型中检测PARP的药理学抑制作用。作为初步数据，研究人员在培养的胰岛细胞中提供了证据，表明PARP激活在氧化剂介导的胰岛细胞损伤和糖尿病心血管并发症的发展中起着关键作用。研究人员现在已经合成了一种有效的PARP抑制剂，作为与自身免疫性糖尿病及其并发症相关的β细胞破坏的实验性治疗的主要开发候选药物。I期部分的主要目的是在糖尿病啮齿动物中进行概念验证体内研究。如果这些研究证实Inotek的PARP抑制剂在糖尿病的链脲佐菌素和NOD模型中非常有效，并可预防糖尿病并发症，则将启动II期部分，重点是正式的临床前安全性测试。在当前SBIR申请的II期部分中，研究者建议使用GLP质量材料进行临床前安全性研究。将开发该化合物的GMP质量合成，并将该化合物配制为口服药物。此外，研究人员建议进行正式的安全性研究，并在项目的第二年在P53小鼠中进行加速致癌性试验。这些后面的研究是必不可少的未来引入一个有效的PARP抑制剂到糖尿病的临床管理。总之，研究人员要求NIH提供资金，以开发一种有效的口服生物可利用的PARS抑制剂，预计该抑制剂可有效降低I型糖尿病的发病率，并减轻高血糖诱导的血管并发症（在已确定的I型和II型糖尿病中）。