Novel Small Molecules For Acute Liver Failure

描述（由申请人提供）：急性肝衰竭（ALF）对临床医生和科学家都构成了挑战。通常与酒精-对乙酰氨基酚综合征相关，其临床过程不可预测且两极分化，大部分病例的结局是死亡。由于缺乏特异性治疗，器官移植是临床上唯一有效的策略。因此，该领域的转化研究已经成熟，可以识别和开发新的治疗策略，以减轻肝细胞死亡，促进肝再生和改善结果。在最好的情况下，这种疗法将加速肝脏再生并排除移植的需要;在最严重的情况下，它们将作为“肝桥”直到移植。大量证据表明，分散因子/肝细胞生长因子（SF/HGF）发挥直接的肝保护作用，并可能用作ALF的治疗药物。然而，以基因或蛋白质疗法的形式使用这种生长因子的可行性由于许多后勤问题而变得复杂。模拟SF/HGF活性的低分子量化合物可以克服这些后勤困难并提供有效的治疗。基于SF/HGF受体c-Met酪氨酸激酶结构域的ATP结合位点的三维结构，并使用合理药物设计与临床前生物学相结合的产品发现引擎，我们已经确定了以酞嗪-1（2 H）-酮支架为中心的SF/HGF样小分子。Ang 1170是该类中的主要成员，它激活SF/HGF受体c-Met，并在迄今为止测试的每种测定中概括了SF/HGF的生物活性。在我们的I期项目下进行的原理验证研究表明，Ang 1170激活肝细胞SF/HGF/c-Met通路，减弱氧化应激诱导的肝细胞死亡，并加速部分肝切除边缘肝的再生。在ALF的哺乳动物模型中，Ang 1170全身预处理降低死亡率，并减轻肝损伤。我们的初步发现具有潜在的临床意义，即延迟Ang 1170治疗，减少肝细胞死亡，刺激肝再生，降低死亡率并减轻ALF中的肝功能障碍。重要的是，Ang 1170在衰竭的边缘肝中具有治疗性。初步安全性研究表明，Ang 1170治疗是安全的，耐受性良好。在单独资金的支持下，一系列正式和全面的监管研究正在进行中，这些研究概述了Ang 1170的遗传毒理学，毒理学和安全药理学。目前的II期申请旨在完成Ang 1170的临床前表征，将充分探索其在ALF临床前模型中的治疗功效;在两个物种中进行的一组急性、体内重复剂量、剂量递增安全性研究将补充这些功效研究。成功完成拟议的监管研究将支持向美国食品药品监督管理局提交的新药研究申请;该申请的批准将允许我们的SF/HGF模拟物Ang 1170的首次临床研究。公共卫生相关性：急性肝衰竭仍然是发病率和死亡率的重要原因。一种小分子肝细胞生长因子模拟物，是肝保护和肝再生是巨大的临床效益。

DESCRIPTION (provided by applicant): Acute liver failure (ALF) constitutes a challenge to clinicians and scientists alike. Commonly associated with the alcohol-acetaminophen syndrome, its clinical course is unpredictable and polarizing, with death as the outcome in a large percentage of cases. Given the lack of specific therapy, organ transplantation is the only clinically effective strategy. Consequently, the field is ripe for translational studies that identify and develop new therapeutic strategies that attenuate hepatocyte death, promote hepatic regeneration and improve outcome. In a best-case scenario, such therapeutics will accelerate liver regeneration and preclude the need for transplantation; in the most severe cases, they will serve as a "hepatic bridge" until transplantation. Significant evidence suggests that scatter factor / hepatocyte growth factor (SF/HGF), exerts direct hepatoprotective effects and can potentially be used as a therapeutic in ALF. However, the feasibility of using this growth factor in the form of gene or protein therapy is compounded by numerous logistical issues. Low molecular weight compounds that mimic the activity of SF/HGF could overcome these logistical difficulties and provide effective therapy. Based on the 3-dimensional structure of the ATP-binding site of the SF/HGF receptor c-Met's tyrosine kinase domain and using a product discovery engine combining rational drug design with preclinical biology, we have identified SF/HGF-like small molecules centered around a phthalazin-1 (2H)- one scaffold. Ang 1170, the lead member within this class, activates the SF/HGF receptor c-Met and has recapitulated the bioactivity of SF/HGF in every assay tested to date. Proof-of-principle studies conducted under our Phase I program indicate that Ang 1170 activates the hepatocyte SF/HGF/c-Met pathway, attenuates oxidative stress-induced hepatocyte death and accelerates regeneration in partially hepatectomized marginal livers. In a mammalian model of ALF, Ang 1170 systemic pretreatment reduces mortality, and attenuates hepatic injury. Of potentially significant clinical relevance is our preliminary findings that delayed treatment with Ang 1170, attenuates hepatocyte death, stimulates liver regeneration, decreases mortality and attenuates liver dysfunction in ALF. Importantly, Ang 1170 is therapeutic in the failing marginal liver. Pilot safety studies suggest that Ang 1170 treatment is safe and well-tolerated. Supported by separate funding, a formal and comprehensive set of regulatory studies profiling the genotoxicology, toxicology and safety pharmacology of Ang 1170 is underway. The present Phase II application, designed to complete the preclinical characterization of Ang 1170, will explore fully its therapeutic efficacy in preclinical models of ALF; a panel of acute, in vivo repeat dose, dose-escalating safety studies in two species will complement these efficacy studies. Successful completion of the proposed regulatory studies will support an Investigational New Drug application to Food and Drug Administration; approval of this application will allow the first clinical studies of our SF/HGF mimetic, Ang 1170. PUBLIC HEALTH RELEVANCE: Acute liver failure remains a significant cause of morbidity and mortality. A small molecule hepatocyte growth factor mimetic that is hepatoprotective and hepatoregenerative is of tremendous clinical benefit.