NITRIC OXIDE SYNTHASE INHIBITOR FOR INTESTINAL POLYPOSIS

用于肠息肉病的一氧化氮合酶抑制剂

• 批准号: 6288497
• 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 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6288497
• 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：（申请人的描述） 氧化物合酶; iNOS）与各种形式的 炎症。 慢性炎症是一种已知的危险因素， 致癌作用 有多条线索表明 诱导型一氧化氮合酶/过氧亚硝基阴离子通路在肠道炎症发病中的作用 应答 在这篇文章中，我们提出了以下证据：（1） 巯基乙基胍（MEG）及其二聚体形式，胍基乙基二硫化物 (GED)（本申请人的专利巯基烷基胍的先导化合物 类化合物系列）是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，和 具有额外的过氧亚硝酸根清除剂活性;和（2）MEG和GED 是具有适当治疗比例的化合物，适用于临床前和 临床开发用于各种形式的炎症。 这些数据， （3）新的初步证据表明， 过氧亚硝基阴离子/诱导型一氧化氮合酶在肠梗阻发病中的相关机制 息肉病为目前的建议提供了有力的支持。 的目的 建议的项目是（1）在小鼠模型中进行确定性的体内研究 使用min/APC模型对肠息肉病进行研究，以测试GED是否 可以减缓或逆转息肉病的发作;（2）执行 在2个种属中进行的GED亚慢性90天毒性研究， 以确定它们是否适用于与以下相关的适应症： 慢性肠道炎症/息肉病。 目前的结果 申请将允许申请第2阶段SBIR资金，以支持： 完成临床前药物试验（以完成 高级毒性测定、病理学、稳定性、药代动力学）， 准备向FDA提交的研究药物申请，以及I期和 II临床试验。 拟议的商业应用： 仅在美国，预防和治疗肠息肉病的有效治疗方法的年预期收入就超过2亿美元。