NOVEL PARS INHIBITOR FOR ACETAMINOPHEN INTOXICATION

扑热息痛的急性肝毒性是一个主要的健康问题，因为这种止痛药是故意过量使用的最常用药物之一。目前对乙酰氨基酚所致肝毒性的治疗方案疗效有限。最近发现的一种炎性损伤机制，即多(ADP-核糖)合成酶(PARS)途径，现已被认为与扑热息痛肝毒性的发病机制密切相关。PARS激活诱导AP-1依赖的促炎基因表达和NAD消耗，导致ATP耗竭、细胞能量衰竭、粒细胞浸润和终末器官损伤。在这项建议中，我们提出了实验证据，表明药物抑制PARS活性和基因切割PARS基因具有强大的抗炎作用，并显著保护对乙酰氨基酚诱导的损伤。伊诺克正在开发一种高效、特异、无毒和专有的PARS抑制剂，5-碘-6-氨基-1，2-苯并吡喃酮(INH_2BP)。INH2 BP需要在临床相关和严格的对乙酰氨基酚中毒实验模型中证明其有效性，才能证明其作为一种预防肝功能衰竭的新型抗炎药的商业化。在这项提案中，我们将测试INH2 BP在不同时间点和剂量水平下的保护作用，并与目前临床治疗的黄金标准N-乙酰半胱氨酸进行比较。指示治疗效果的生物学终点将包括中性粒细胞渗透、组织学损害、聚腺苷二磷酸核糖形成、脂质过氧化和血清转氨酶升高。INH2 BP在暴露后范例中在这一模型中有效的证明将代表着治疗对乙酰氨基酚中毒的新方案设计的突破，并将证明其进一步的商业开发是合理的。拟议的商业应用：对乙酰氨基酚中毒的一种新的、有效的治疗方法在国内市场每年估计为2.5亿美元。据估计，全球市场规模为8亿美元。目前的市场进入者疗效有限：大量扑热息痛中毒经常导致暴发性肝衰竭，需要进行原位肝移植。INH2 BP可能是当前治疗方案的第一个高度有效和成功的辅助疗法；SBIR第一和第二阶段的资金将允许在4年内进入市场。

The acute hepatotoxicity of acetaminophen is a major health concern since this analgesic is one of the most commonly used drugs in intentional overdose. Current treatment regimens for acetaminophen-induced hepatotoxicity have limited efficacy. A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has now been strongly implicated in the pathogenesis of acetaminophen-induced hepatotoxicity. PARS activation induces AP-1 dependent pro-inflammatory gene expression and NAD consumption, resulting in ATP depletion, cellular energetic failure, granulocytic infiltration, and end-organ injury. In this proposal, we present experimental evidence that pharmacologic inhibition of PARS activity and genetic ablation of the PARS gene have potent anti-inflammatory effects and dramatically protect against acetaminophen-induced injury. Inotek is developing a highly potent, specific, non-toxic, and proprietary PARS inhibitor, 5-iodo-6-amino-1,2-benzopyrone (INH2BP). INH2BP requires demonstration of efficacy in a clinically relevant and stringent experimental model of acetaminophen intoxication in order to justify its commercialization as a novel anti-inflammatory agent for the prevention of liver failure. In this proposal, we will test the protective effect of INH2BP, administered at various timepoints and dose levels, in comparison with N- acetyl cysteine, the current gold standard of clinical therapy. Biological endpoints, indicative of therapeutic efficacy, will include neutrophil infiltration, histiologic damage, poly ADP-ribose formation, lipid peroxidation, and serum transaminasemia. The demonstration that INH2BP is effective in this model in a post-exposure paradigm would represent a breakthrough in the design of novel regimens for the treatment of acetaminophen intoxication and would justify its further commercial development. PROPOSED COMMERCIAL APPLICATIONS: The domestic market for a novel, effective therapy for acetaminophen intoxication is estimated at $250 million per annum. Global markets are estimated at $800 million. Current market entrants have limited efficacy: massive acetaminophen intoxication frequently results in fulminant liver failure necessitating orthotopic liver transplantation. INH2BP may represent the first highly potent and successful adjunct to the current therapeutic regimen; funding of SBIR Phases I and II will allow for market entry in 4 years.