Poly(ADP-ribose) synthetase inhibition and diabetes

描述(由申请人提供)：当前的申请是INOTK公司快速通道SBIR拨款的第一阶段，建议建立一项聚(ADP-核糖)聚合酶(PARP)激活在I型糖尿病及其并发症的发病机制中参与的概念验证，并在糖尿病及其并发症的小鼠模型中测试PARP的药理抑制效果。作为初步数据，研究人员提出了培养的胰岛细胞中的证据，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发挥关键作用。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细胞破坏及其并发症的实验性治疗的主要开发候选药物。第一阶段组件的中心目标是在糖尿病啮齿动物身上进行概念验证研究。如果这些研究证实伊诺克的PARP抑制剂在糖尿病的链脲佐菌素和NOD模型中非常有效，并预防糖尿病并发症，将触发第二阶段组件，该组件将专注于正式的临床前安全性测试。在目前SBIR应用的第二阶段，研究人员建议使用GLP优质材料进行临床前安全性研究。将开发一种GMP质量的化合物合成方法，并将该化合物制成口服药物。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小鼠身上进行加速致癌试验。这些后一项研究对于未来将一种有效的PARP抑制剂引入糖尿病的临床治疗是至关重要的。总而言之，研究人员要求美国国立卫生研究院提供资金，以开发一种有效的口服生物可用PARS抑制剂，预计它将有效地降低I型糖尿病的发病率，并减轻高血糖引起的血管并发症(已确定的I型和II型糖尿病)。

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).