NOVEL ANTIOXIDANTS FOR THERAPY OF PERIODONTAL DISEASE

在最近的研究中，我们的研究小组已经提出证据，巯基乙基胍（MEG）和相关的药物，如其二聚体形式的胍基乙基二硫化物（GED）是有希望的诱导型一氧化氮合酶（iNOS）抑制剂，对诱导型异构体（iNOS）具有选择性。此外，我们获得的数据表明，这些化合物是细胞毒性氧化剂过氧亚硝酸盐的清除剂。基于一氧化氮和过氧亚硝酸盐在牙周病发病机制中的作用，我们目前正在开发第一代用于牙周病的MEG类候选药物。最近的体内实验数据表明，MEG和GED在大鼠结扎性牙龈炎/牙周炎模型中有效抑制炎症过程。此外，我们提出的数据表明MEG和GED的适当治疗比例。Inotek公司正在开发用于牙周病实验性治疗的巯基烷基胍。Inotek目前还在开发“第二代”iNOS抑制剂/过氧亚硝酸盐清除剂化合物，例如硒乙基胍和硒丙基胍。初步体外实验数据表明，将硫基替换为硒可使化合物与过氧亚硝酸盐的反应活性提高约100倍。此外，硒代乙基胍保持其iNOS抑制作用。本研究的第一个目的是合成硒基胍，并进行体外研究，以表征其作为NOS抑制剂的作用，确定其异构体选择性和过氧亚硝酸盐清除活性。该研究的第二个目的是在牙周病大鼠模型中测试硒基胍，其中NO和过氧亚硝酸盐在疾病发展中起关键作用。目前申请的结果将允许申请2期SBIR资金，以支持临床前药物测试（在动物模型中进一步测试，高级毒性测定，病理学，稳定性，药代动力学，体内疗效），向FDA申请IND，以及1期临床试验)。建议的商业应用：仅在美国，预防和治疗牙周病的有效疗法的年预期收入就超过300亿美元。

In recent studies, our group have presented evidence that mercaptoethylguanidine (MEG) and related agents such as its dimeric form guanidinoethyldisulfide (GED) are promising inducible nitric oxide synthase (iNOS) inhibitors with selectivity for the inducible isoform (iNOS). In addition, we have obtained data, which demonstrated that these compounds are scavengers of the cytotoxic oxidant peroxynitrite. Based on the role NO and peroxynitrite plays in the pathogenesis of periodontal disease, we are currently developing a first-generation candidate of the MEG class for periodontal diseases. Recent in vivo data demonstrated that MEG and GED are effective in suppressing the course of inflammation in the ligature-induced gingivitis/periodontitis model in the rat. Furthermore, we present data demonstrating the appropriate therapeutic ratio of MEG and GED. Inotek Corporation is in the process of the development of mercaptoalkylguanidines for the experimental therapy of periodontal disease. Inotek is now also developing a "second generation" class of iNOS inhibitor/peroxynitrite scavenger compounds, exemplified by selenoethylguanidine and selenopropylguanidine. Preliminary in vitro data suggest that substitution of the sulfur group to selenium increases the reactivity of the compound with peroxynitrite by about 100-fold. In addition, selenoethylguanidine maintains its iNOS inhibitory effects. The first aim of the current study is to synthesize selenoguanidines, and perform in vitro studies to characterize its effects as NOS inhibitor, determine their isoform selectivity, and their peroxynitrite scavenging activity. The second aim of the study is to test selenoguanidines in a rat model of periodontal disease, where NO and peroxynitrite play a key role in disease development. The results of the present application will permit application for Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (further testing in animal models, advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), IND application to the FDA, and Phase 1 clinical trial). PROPOSED COMMERCIAL APPLICATIONS: The annual anticipated revenues for an effective therapeutic to prevent and treat periodontal disease is over $30 billion in the US alone.