ANIMAL TRIAL OF SEPTIC SHOCK WITH A NOVEL PARS INHIBITOR

一氧化氮（NO）和过氧亚硝酸盐是反应性的、短命的物质，是休克和缺血再灌注时细胞损伤的重要介质。特别是，过氧亚硝酸盐，一种由超氧化物和一氧化氮产生的短寿命强氧化剂，可以启动一系列细胞毒性过程。清除一氧化氮或过氧亚硝酸盐的药物，或阻止一氧化氮或过氧亚硝酸盐诱导的血管和细胞毒性过程的药物，在单独使用或与其他药物联合使用时，都是治疗休克的有用工具。Inotek公司正在开发一种独特的工具，5-氨基-6-碘-1,2-苯并吡喃酮（INH2BP），一种有效的细胞渗透性核酶聚（adp -核糖）合成酶（PARS）抑制剂。细胞培养和啮齿动物休克模型的研究表明，内毒素诱导过氧亚硝酸盐的产生、DNA损伤和随后的PARS激活。这些过程可导致急性细胞功能障碍和细胞死亡。因此，在啮齿动物内源性休克模型中，药物抑制PARS可改善生存和血管功能。本课题的具体目的是合成大量的INH2BP，并在脓毒性休克的大型动物模型中进行研究，以获得该药物可以减轻脓毒性休克的组织损伤，改善血流动力学和生存率的明确原理证明。申请人的目的是测试INH2BP抗冲击的潜力。目前申请的结果将提供最终的原理证明，并允许申请二期SBIR资金，以支持临床前药物测试（高级毒性测定、病理、稳定性、药代动力学、体内疗效）、向FDA申请研究药物和一期临床试验。拟议的商业应用：全球有效、安全的抗休克药物市场估计为每年200亿美元，以200万患者为基础，每个疗程1万美元。预计在未来15年内，对有效治疗休克的需求将稳步增长。SBIR第一期和第二期的资金将允许在3.5年内进入市场。

Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of cellular injury in shock and ischemia-reperfusion. In particular, peroxynitrite, a short-lived potent oxidant, produced from superoxide and NO, can initiate a range of cytotoxic processes. Agents which scavenge NO or peroxynitrite, or agents that prevent NO-or peroxynitrite induced vascular and cytotoxic processes can be useful tools in treating shock, when applied alone, or in combination with other agents. Inotek Corporation is developing a unique tool, 5-amino-6-iodo-1,2-benzopyrone (INH2BP), a potent, cell-permeable inhibitor of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Studies in cell culture and in rodent models of shock demonstrate that endotoxin induces peroxynitrite generation, DNA injury, and subsequent PARS activation. These processes can lead to acute cellular dysfunction and cell death. Accordingly, in rodent models of endotoxic shock, pharmacological inhibition of PARS improves survival and vascular function. The specific aim of the present proposal is to synthesize large quantities of INH2BP, and perform studies in a large animal model of septic shock in order to obtain definitive proof of principle that this agent can reduce the tissue injury and improve hemodynamics and survival in septic shock. The applicants' intention is to test the INH2BP for its potential against shock. The results of the present application will provide ultimate proof of principle and permit application for Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA and Phase 1 clinical trial. PROPOSED COMMERCIAL APPLICATION: Worldwide the market for an effective, safe anti-shock pharmaceutical is estimated to be $20 billion per year, based upon 2 million patients @ $10,000 per treatment course. The demand for effective treatment of shock is expected to increase steadily over the next 15 years. Funding of SBIR Phase I and II will allow for market entry in 3.5 years.