PARS INHIBITOR FOR THE THERAPY OF CIRCULATORY SHOCK

描述(逐字摘自申请者摘要)：基于承诺 体外和体内数据，申请者正在开发新的类别 具有抗休克作用和显著治疗潜力的化合物。 在这项提案中，我们提出了证据表明，选定的新型抑制剂 聚对位核糖合成酶(PARs)是(1)细胞保护剂和抑制剂 体外氧化剂诱导的细胞坏死，(2)产生 巨噬细胞来源的体外促炎介质，(3)强大的抗休克作用 大鼠和小鼠的全身性炎症，最后(4)，一种选择的，有效的 这种新型的PARS抑制剂(例如PJ34)的成员提供了戏剧性的 猪严重血流动力学崩溃和休克模型的保护作用。这些 观察结果，加上申请人的实验室和几个 其他研究小组，证明了PARS基因敲除小鼠大量 防止各种形式的冲击，集体支持申请人的 建议，即PARS的有效药物抑制剂可以是 作为一类新型的抗休克药物而开发。申请人的意图是 开发PJ34作为抗休克药物。当前的第一个具体目标 建议在啮齿动物和猪的系统中进行额外的研究， 要确定PJ34的干预窗口，最合适的剂量是 行政管理，并确定停止使用 那个经纪人。该提案的另一个具体目标是合成大型 GMP-PJ34化合物的量，并作为静脉注射使用 可注射的。这些研究将在第二年进行，随后 正式的临床前毒性研究，以及第一阶段正常人研究 志愿者。目前的项目将使申请者能够在 两年，接近#年第二阶段疗效试验开始时的水平 败血症患者。 建议的商业应用： 不可用

DESCRIPTION (Verbatim from the Applicant's Abstract): Bases on promising in vitro and in vivo data, the applicants are developing novel classes of compounds with anti-shock effects, and with significant therapeutic potential. In this proposal, we present evidence that selected novel inhibitors of poly(DP-ribose) synthetase (PARS) are (1) cytoprotective agents and inhibitors of oxidant-induced cell necrosis in vitro, (2) inhibitors of the production of macrophage-derived pro-inflammatory mediators in vitro, (3) potent anti-shock systemic inflammation in rats and mice and, finally (4), a selected, potent member of this novel class of PARS inhibitors (e.g. PJ34) provides dramatic protection in a porcine model of severe homodynamic collapse and shock . These observations, coupled with data from the applicant's laboratories and several other research groups, demonstrating that PARS knockout mice are massively protected against various forms of shock, collectively support the applicant's proposal, which is that potent pharmacological inhibitors of PARS can be developed as a novel class of anti-shock agents. The applicant's intend to develop PJ34 as an anti-shock drug. The first specific aims of the present proposal is to perform additional studies in the rodent and porcine system with PJ34 to determine the window of intervention, the most appropriate dose of administration, and to determine the optimal strategy for discontinuation of the agent. An additional specific aim of the proposal is to synthesize large GMP-quantities of the PJ34 compound, and to formulate as an intravenous injectable. These studies will be performed in the second year, followed by formal preclinical toxicity studies, and Phase I a study in normal human volunteers. The current project will enable the applicants to move forward in two years, near to the level of the beginning of Phase II efficacy trial in septic patients. PROPOSED COMMERCIAL APPLICATION: Not Available