Development of Compounds for the Prevention and Treatment of Rhabdomyolysis

预防和治疗横纹肌溶解症的化合物的开发

基本信息

批准号：
8834621
负责人：
JOHN Alexander OATES
金额：
$ 37.41万
依托单位：
VDDI PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-26 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8834621
关键词：
Accounting Acetaminophen Acute Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Address Affect Animals Blood Circulation Caring Clinical Coma Crush Injury Data Deposition Development Dose Drug Formulations Drug Kinetics Earthquakes Electrons Enzymes Event Explosion F2-Isoprostanes Goals Hemeproteins Hepatotoxicity Hospitalization Human Hyperthermia In Vitro Injury Investigation Ischemia Kidney Kidney Failure Lead Legal patent Length Life Lipid Peroxidation Liver Liver Failure Measures Metabolism Methodology Methods Military Personnel Modeling Morbidity - disease rate Muscle Myocardial Reperfusion Injury Myoglobin Myopathy National Institute of Diabetes and Digestive and Kidney Diseases Operative Surgical Procedures Orphan Orphan Drugs Oxidation-Reduction Peroxidases Pharmaceutical Preparations Phase Prevention Process Prostaglandin-Endoperoxide Synthase Rattus Renal Blood Flow Research Rhabdomyolysis Risk Rodent Safety Seizures Series Small Business Technology Transfer Research Synthesis Chemistry Testing Therapeutic Agents Toxicokinetics Translations Trauma United States Universities Vasoconstrictor Agents Work acute stroke analog base combat commercial application commercialization comparative efficacy cost cytotoxic cytotoxicity design effective therapy efficacy testing electron donor in vitro Assay in vivo inhibitor/antagonist meetings metabolic abnormality assessment mortality mouse model pre-clinical preclinical study prevent programs public health relevance scaffold sickle cell crisis small molecule success tubular necrosis vasoconstriction vehicular accident

项目摘要

DESCRIPTION (provided by applicant): The goal of this Phase I STTR project is to establish the feasibility of developing a small-molecule therapeutic agent designed to prevent rhabdomyolysis-induced renal failure. Rhabdomyolysis accounts for 7% to 10% of cases of renal failure in the US. Rhabdomyolysis results from muscle injury that leads to the release of myoglobin, which is then deposited in the kidney. Acute renal injury and renal failure results. Often caused by crush injuries such as those that occur with earthquakes, explosive injuries (especially to military personnel) and other trauma, rhabdomyolysis also can result from hyperthermia, seizures, muscle ischemia, coma, or statin-induced myopathy. No effective means currently exist to prevent the kidney failure that results from rhabdomyolysis. Myoglobin deposited in the kidney undergoes redox cycling, generating radicals that produce lipid peroxidation-the products of which cause vasoconstriction and tubular necrosis. Consequently, the VDDI STTR team, which includes experts from Vanderbilt University, has designed a project based on strong preliminary data that is focused on taking the first steps toward preventing the severe damage that results from rhabdomyolysis. During preliminary work we were able to demonstrate that acetaminophen inhibited the cyclooxygenase enzymes by reducing the peroxidase radicals required for their catalytic activity. We consequently found that acetaminophen also reduces the radicals generated by redox cycling of many hemeprotein peroxidases, including myoglobin. This led to the discovery that acetaminophen prevents the development of acute renal failure in a rat model of rhabdomyolysis. Because the intrinsic hepatotoxicity associated with acetaminophen limits its utility, we initiated a discovery program that yielded compounds which, like acetaminophen, inhibit the lipid peroxidation resulting from redox cycling of myoglobin but have structural differences that suggest they would not be metabolized to the type of electrophilic metabolites responsible for acetaminophen-induced hepatotoxicity. Three patent-pending compounds originating from 3 structurally distinct series have emerged from this process that are potent inhibitors of myoglobin-induced lipid peroxidation and are not cytotoxic in vitro. For this Phase I STTR project we propose to 1) determine whether these compounds are free of drug class-induced hepatotoxicity, and 2) evaluate them for efficacy in the rat model of rhabdomyolysis in comparison with acetaminophen. As a basis for these studies and for translation to clinical dosing and assessment, the metabolism and pharmacokinetics of the compounds will be characterized in multiple species. A lead compound will then be selected for follow- on preclinical development, as required by STTR solicitation PA-14-054. Phase I success will lead to a larger Phase II project focused on the studies needed to support an IND filing and ultimate commercialization of this new "orphan" treatment for rhabdomyolysis-along with commercial applications for ischemia-reperfusion myocardial injury, surgical or hemohorragic stroke, acute Sickle Cell Crisis, and many others.

描述（由申请人提供）：该第一阶段 STTR 项目的目标是确定开发一种小分子治疗剂的可行性，该治疗剂旨在预防横纹肌溶解引起的肾衰竭，横纹肌溶解引起的肾衰竭占肾衰竭病例的 7% 至 10%。在美国，横纹肌溶解症是由肌肉损伤导致肌红蛋白释放而引起的，然后肌红蛋白沉积在肾脏中，通常由挤压伤等引起。横纹肌溶解症是由地震、爆炸伤（特别是军事人员）和其他创伤引起的，高热、癫痫、肌肉缺血、昏迷或他汀类药物引起的肌病也可能导致横纹肌溶解症，目前尚无有效的方法来预防由此引起的肾衰竭。沉积在肾脏中的肌红蛋白经历氧化还原循环，产生自由基，产生脂质过氧化，其产物导致血管收缩和肾小管坏死。在前期工作中，包括范德比尔特大学专家在内的 VDDI STTR 团队根据强有力的初步数据设计了一个项目，重点是采取初步措施预防横纹肌溶解症造成的严重损害。对乙酰氨基酚通过减少催化活性所需的过氧化物酶自由基来抑制环氧合酶，因此我们发现对乙酰氨基酚还可以抑制许多氧化还原循环产生的自由基。这导致发现对乙酰氨基酚可以预防横纹肌溶解症大鼠模型中急性肾衰竭的发生，因为与对乙酰氨基酚相关的内在肝毒性限制了其用途，我们启动了一项发现计划，该计划产生了与对乙酰氨基酚类似的化合物。，抑制肌红蛋白氧化还原循环引起的脂质过氧化，但结构差异表明它们不会被代谢为负责对乙酰氨基酚诱导的肝毒性的三种正在申请专利的化合物源自该过程，它们是肌红蛋白诱导的脂质过氧化的有效抑制剂，并且在该第一阶段 STTR 项目中没有细胞毒性。我们建议 1) 确定这些化合物是否不存在药物类诱导的肝毒性，2) 评估它们在大鼠横纹肌溶解模型中的功效作为这些研究以及转化为临床剂量和评估的基础，将根据多个物种的代谢和药代动力学特征选择先导化合物进行后续临床前开发。 STTR 征集 PA-14-054 的成功将导致一个更大的第二阶段项目，重点是支持 IND 申请和最终商业化这种横纹肌溶解症新“孤儿”疗法所需的研究。商业应用可用于缺血再灌注心肌损伤、手术或出血性中风、急性镰状细胞危象等。