Novel antioxidants for periodontal disease

产品说明：（由申请人提供）当前申请代表标题为“用于治疗牙龈炎的新型药物”的第I期NIH SBIR资助1 R43 DE 13625的第2期延续的第一次修订。申请人是研究和临床前开发用于牙周病发展的基于一氧化氮的新型创新技术的领导者。在I期申请中，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亚型（iNOS）具有选择性，并具有增加的自由基清除活性，并建议在大鼠中进行临床前研究，以证明其在牙龈炎中的疗效。在I期研究中进行的研究证实了牙周炎中iNOS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的有效抗炎作用。此外，我们已经证明了在相同的实验模型与FP 15，一种新的过氧腈分解催化剂，与PJ 34，多功能核酶聚（ADP-核糖）聚合酶的抑制剂的显着疗效。这些额外的策略专门针对牙周炎性疾病的NO相关下游炎症途径。在当前的申请中，我们建议对SEG、FP 15和PJ 34进行临床前研究，以开发作为牙龈炎/牙周炎治疗方法的主要候选药物。本发明的具体目的是合成大量的三种测试化合物，并在牙龈炎和牙周炎的比格犬模型中进行研究，以获得药物可以减少组织损伤和炎症的确切原理证明。基于有效性和安全性数据，将选择一种先导药物用于进一步开发牙龈炎和牙周炎的实验性治疗。本次申报的其他目的是完成临床前药物试验（GMP合成、高级制剂、稳定性和局部刺激性试验），以达到向FDA申请研究药物的阶段。在整个工作过程中，Inotek公司与北卡罗来纳州大学的科学家合作，该大学是牙周炎实验治疗的领先组织，并与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.