Novel Small Molecules For Acute Liver Failure

治疗急性肝衰竭的新型小分子

• 批准号: 7503966
• 负责人: PRAKASH NARAYAN
• 金额: $ 107.93万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7503966
• 关键词: Acetaminophen; Acute; Acute Liver Failure; Age; Agonist; Alcohols; Attenuated; Binding Sites; Biodistribution; Biological Assay; Biology; Bromodeoxyuridine; Canis familiaris; Cessation of life; Chemicals; Class; Clinic; Clinical; Clinical Research; Clinical Trials; Complement; Condition; Data Analyses; Development; Dose; Drug Design; Drug Kinetics; Drug or chemical Tissue Distribution; Enzymes; Ethanol; Experimental Models; Extracellular Domain; Failure; Fatty Liver; Funding; Future; Generations; Genes; Growth Factor; Head; Hepatic; Hepatic Insufficiency; Hepatocyte; Hepatocyte Growth Factor; Histopathology; Hospitalization; Hour; Human; In Vitro; Injury; Intellectual Property; International; Intravenous; Investigational New Drug Application; Kentucky; Knowledge; Laboratories; Laboratory Research; Lawyers; Lead; Legal patent; Letters; Libraries; Life; Liver; Liver Dysfunction; Liver Failure; Liver Fibrosis; Liver Regeneration; Liver diseases; Medicine; Metabolism; Modeling; Molecular Weight; Morbidity - disease rate; Natural regeneration; Numbers; Operative Surgical Procedures; Organ; Organ Transplantation; Orphan Drugs; Outcome; Oxidative Stress; PCNA gene; Paper; Pathway interactions; Patients; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Play; Pre-Clinical Model; Production; Protein Tyrosine Kinase; Proteins; Proteolysis; Proto-Oncogene Protein c-met; Public Health; Range; Rattus; Relative (related person); Research; Research Design; Resources; Rivers; Role; Safety; Scheme; Scientist; Series; Serum; Site; Solutions; Standards of Weights and Measures; Syndrome; Testing; Therapeutic; Therapeutic Effect; Thioacetamide; Toxic effect; Toxicology; Training; Translating; Translational Research; Transplant Surgeon; Transplantation; Treatment Efficacy; Tyrosine Kinase Domain; United States Food and Drug Administration; Universities; Wisconsin; Wistar Rats; Work; absorption; base; clinically relevant; cost; day; design; expectation; experience; feeding; human MET protein; improved; in vivo; in vivo Model; innovation; liver transplantation; member; mimetics; mortality; novel; novel therapeutics; pharmacophore; pre-clinical; programs; prospective; research study; scaffold; small molecule; symposium; three dimensional structure; translational study

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.

描述（由申请人提供）：急性肝衰竭（ALF）对临床医生和科学家来说都是一个挑战。通常与酒精-对乙酰氨基酚综合征相关，其临床病程不可预测且两极分化，大部分病例的结果是死亡。由于缺乏特异性治疗方法，器官移植是临床上唯一有效的策略。因此，转化研究领域已经成熟，可以识别和开发新的治疗策略，以减轻肝细胞死亡、促进肝再生和改善预后。在最好的情况下，这种疗法将加速肝脏再生并消除移植的需要；在最严重的情况下，它们将充当“肝桥”直至移植。大量证据表明，分散因子/肝细胞生长因子 (SF/HGF) 具有直接的保肝作用，有可能用作 ALF 的治疗剂。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因许多后勤问题而变得更加复杂。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 ATP 结合位点的 3 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，我们鉴定了以 phaazin-1 (2H)-one 支架为中心的 SF/HGF 样小分子。 Ang 1170 是此类中的主要成员，可激活 SF/HGF 受体 c-Met，并在迄今为止测试的每项检测中重现 SF/HGF 的生物活性。在我们的第一阶段计划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，减轻氧化应激诱导的肝细胞死亡，并加速部分肝切除的边缘肝脏的再生。在 ALF 哺乳动物模型中，Ang 1170 全身预处理可降低死亡率并减轻肝损伤。具有潜在重要临床意义的是我们的初步发现，即延迟使用 Ang 1170 治疗，可减少 ALF 中肝细胞死亡、刺激肝再生、降低死亡率并减轻肝功能障碍。重要的是，Ang 1170 对衰竭的边缘肝具有治疗作用。试点安全研究表明 Ang 1170 治疗是安全且耐受性良好的。在单独资金的支持下，一套正式且全面的监管研究正在进行中，该研究对 Ang 1170 的基因毒理学、毒理学和安全药理学进行了分析。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；对两个物种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食品和药物管理局提交研究性新药申请；该申请的批准将允许对我们的 SF/HGF 模拟物 Ang 1170 进行首次临床研究。 公共健康相关性：急性肝衰竭仍然是发病和死亡的一个重要原因。具有保肝作用和肝再生作用的小分子肝细胞生长因子模拟物具有巨大的临床益处。