A NITRIC OXIDE SYNTHASE INHIBITOR FOR INTESTINAL POLYPOS

一种治疗肠息肉的一氧化氮合酶抑制剂

• 批准号: 6497460
• 负责人: Garry John Southan
• 金额: $ 25万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497460
• 关键词: antiinflammatory agents; carcinogenesis inhibitor; chemoprevention; drug design /synthesis /production; enzyme inhibitors; guanidines; inflammation; intestine neoplasm; laboratory mouse; nitric oxide synthase; peroxynitrites; protein isoforms

DESCRIPTION: (Applicant's Description) oxide synthase; iNOS) has been implicated in the pathogenesis of various forms of inflammation. Chronic inflammation is a known risk factor for carcinogenesis. There are multiple lines of evidence implicating the iNOS/peroxynitrite pathway in the pathogenesis of intestinal inflammatory responses. In this proposal, we present evidence that (1) mercaptoethylguanidine (MEG), and its dimeric form, guanidinoethyldisulfide (GED) (lead compounds of the applicants' proprietary mercaptoalkylguanidine class of compound series) are promising nitric oxide synthase (NOS) inhibitors with selectivity for the inducible nitric oxide synthase isoform (iNOS), and with an additional peroxynitrite scavenger activity; and (2) that MEG and GED are compounds of appropriate therapeutic ratio, suitable for preclinical and clinical development for various forms of inflammation. These data, combined with (3) novel preliminary evidence implicating the role of the peroxynitrite/iNOS related mechanisms in the pathogenesis of intestinal polyposis lend strong support to the current proposal. The aim of the proposed project is (1) to perform definitive in vivo studies in murine models of intestinal polyposis using the min/APC model in order to test whether GED can slow down or reverse the onset of the polyposis; and (2) to perform subchronic 90-day toxicity studies with GED in 2 species with the compounds in order to determine whether they are suitable for indications related to chronic intestinal inflammation/polyposis. The results of the present application will permit application for Phase 2 SBIR funding to support: completion of pre-clinical pharmaceutical testing (in order to complete advanced toxicity determinations, pathology, stability, pharmacokinetics), preparation of investigational drug application to the FDA, and a Phase I and II clinical trials. PROPOSED COMMERCIAL APPLICATIONS: The annual anticipated revenues for an effective therapeutic to prevent and treat intestinal polyposis is over $200 million in the US alone.

描述：(申请人描述) 一氧化氮合酶(INOS)参与多种形式的致病过程。 发炎的症状。慢性炎症是已知的危险因素 致癌。有多条证据表明 INOS/过氧亚硝酸盐通路在肠炎发病机制中的作用 回应。在这项提案中，我们提出证据：(1) 硫代乙基胍(Meg)及其二聚体--硫代乙基二硫 (GED)(申请人专有的硫代烷基胍的先导化合物 化合物类)是很有前途的一氧化氮合酶(NOS)抑制剂 对诱导型一氧化氮合酶异构体(INOS)具有选择性，以及 具有额外的过氧亚硝酸盐清除剂活性；以及(2)MEG和GED 是治疗比例适当的化合物，适用于临床前和 临床发展为各种形式的炎症。这些数据加在一起 (3)新的初步证据表明 过氧亚硝酸盐/诱导型一氧化氮合酶在肠道发病机制中的作用 息肉为目前的提议提供了强有力的支持。该计划的目的是 拟议的项目是(1)在小鼠模型中进行明确的活体研究 使用MIN/APC模型对肠息肉病进行评估，以测试GED 可以延缓或逆转息肉病的发病；以及(2)执行 用GED对2个物种进行的90天亚慢性毒性研究 以确定它们是否适合与以下相关的适应症 慢性肠炎/息肉病。目前的结果是 申请将允许申请第二阶段SBIR资金，以支持： 完成临床前药物测试(以便完成 高级毒性测定、病理学、稳定性、药代动力学)， 向FDA提交研究药物申请的准备工作，以及第一阶段和 II临床试验。 建议的商业应用： 仅在美国，预防和治疗肠道息肉病的有效疗法的年预期收入就超过2亿美元。