Novel antioxidants for periodontal disease

描述：(由申请人提供)目前的申请是第一阶段NIH SBIR Grant 1 R43 DE13625的第二阶段延续的第一次修订，题为“一种治疗牙龈炎的新试剂”。申请者是研究和临床前开发新的、基于一氧化氮的牙周病创新技术的领先者。在第一阶段的应用中，我们提出了证据表明，硒乙基胍(SEG)是一种有前途的一氧化氮合酶(NOS)抑制剂，对诱导型一氧化氮合酶(INOS)具有选择性，并具有更高的自由基清除剂活性，并建议在大鼠身上进行临床前研究，以证明其对牙周炎的疗效。在I期研究中进行的研究证实了iNOS在牙周炎中的表达和过氧亚硝酸盐的产生，并证明了SEG在结扎诱导的牙周炎大鼠模型中具有强大的抗炎作用。此外，在相同的实验模型中，我们已经证明了使用新型过氧氮基分解催化剂FP15和多功能核酶多聚(ADP-核糖)聚合酶抑制剂PJ34的显著效果。这些额外的策略特别针对牙周炎性疾病的NO相关下游炎症通路。在目前的应用中，我们建议对SEG、FP15和PJ34进行临床前研究，以开发一种治疗牙周炎/牙周炎的主要候选药物。本提案的具体目的是合成大量的这三种测试化合物，并在Beagle狗的牙周炎和牙周炎模型上进行研究，以获得明确的原理证据，即这些药物可以减少组织损伤和炎症。根据疗效和安全性数据，将选择一种先导剂进行进一步开发，用于牙周炎和牙周炎的实验性治疗。目前提交的其他目标是完成临床前药物测试(GMP合成、先进配方、稳定性和局部刺激性测试)，达到向FDA申请研究药物的阶段。在整个工作过程中，伊诺克公司与北卡罗来纳大学的科学家以及领先的合同研究组织合作，进行GMP合成、配方工作和GLP动物安全性测试。

DESCRIPTION: (provided by the applicant) The current application represents the first revision of a Phase 2 continuation of the Phase I NIH SBIR Grant 1 R43 DE13625 entitled "A novel agent for the therapy of gingivitis". The applicants are leaders in the research and preclinical development of novel, nitric oxide based innovative technologies for the development of periodontal disease. In the Phase I application, we have presented evidence that selenoethylguanidine (SEG) is a promising nitric oxide synthase (NOS) inhibitor with selectivity for the inducible nitric oxide synthase isoform (iNOS), and with an increased free radical scavenger activity, and proposed to perform pre-clinical studies in the rat to demonstrate its efficacy in gingivitis. The studies performed in the Phase I studies confirmed iNOS expression and peroxynitrite generation in periodontitis, and demonstrated the potent anti-inflammatory effects of SEG in a rat model of ligature-induced periodontitis. Further, we have demonstrated marked efficacy in the same experimental model with FP15, a novel peroxynitritie decomposition catalyst, and with PJ34, an inhibitor of the multifunctional nuclear enzyme poly(ADP-ribose) polymerase. These additional strategies specifically target NO-related downstream inflammatory pathways of periodontal inflammatory disease. In the current application, we propose to perform pre-clinical studies with SEG, FP15 and PJ34 in order to develop a lead candidate as treatments for gingivitis/periodontitis. The specific aims of the present proposal are to synthesize large quantities of the three test compounds, and perform studies in beagle dog models of gingivitis and periodontitis in order to obtain definitive proof of principle that the agents can reduce the tissue injury and inflammation. Based on the efficacy and safety data, a lead agent will be selected for further development for the experimental therapy of gingivitis and periodontitis. Additional aims of the current submission are to complete the pre-clinical pharmaceutical testing (GMP synthesis, advanced formulation, stability, and local irritation tests), to reach the stage of investigational drug application to the FDA. Throughout the work, Inotek Corporation collaborates with scientists at the University of North Carolina, a leading group in the experimental therapy of periodontal inflammation, as well as with leading contract research organizations to conduct GMP synthesis, formulation work and GLP animal safety testing.