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

• 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
• 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

 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）：本I期STTR项目的目标是确定开发一种旨在预防横纹肌溶解症诱导的肾衰竭的小分子治疗剂的可行性。横纹肌溶解症占美国肾衰竭病例的7%至10%。横纹肌溶解症是由于肌肉损伤导致肌红蛋白释放，然后沉积在肾脏中。急性肾损伤和肾衰竭结果。横纹肌溶解症通常由挤压伤引起，如地震、爆炸伤（特别是军事人员）和其他创伤，也可能由高热、癫痫发作、肌肉缺血、昏迷或他汀类药物诱导的肌病引起。目前还没有有效的方法来预防横纹肌溶解引起的肾衰竭。沉积在肾脏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，其产物引起血管收缩和肾小管坏死。因此，VDDI STTR团队，其中包括来自范德比尔特大学的专家，已经设计了一个基于强有力的初步数据的项目，该项目的重点是采取第一步，以防止横纹肌溶解导致的严重损害。在初步工作中，我们能够证明对乙酰氨基酚通过减少其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，对乙酰氨基酚也减少了许多血红素蛋白过氧化物酶，包括肌红蛋白的氧化还原循环产生的自由基。这导致了对乙酰氨基酚在横纹肌溶解大鼠模型中预防急性肾衰竭的发现。由于与对乙酰氨基酚相关的固有肝毒性限制了其效用，我们启动了一项发现计划，该计划产生的化合物与对乙酰氨基酚一样，抑制肌红蛋白氧化还原循环引起的脂质过氧化，但具有结构差异，表明它们不会代谢为对乙酰氨基酚诱导的肝毒性的亲电代谢物类型。来自3个结构不同系列的三种正在申请专利的化合物已经从该过程中出现，它们是肌红蛋白诱导的脂质过氧化的有效抑制剂，并且在体外没有细胞毒性。对于该I期STTR项目，我们建议1）确定这些化合物是否无药物类诱导的肝毒性，2）评价其在大鼠横纹肌溶解模型中与对乙酰氨基酚相比的疗效。作为这些研究的基础，以及转化为临床给药和评估的基础，将在多个种属中表征化合物的代谢和药代动力学。然后根据STTR征集PA-14-054的要求，选择先导化合物进行后续临床前开发。I期的成功将导致一个更大的II期项目，重点是支持IND申请和最终商业化的研究，这种新的“孤儿”治疗横纹肌溶解症，以及缺血再灌注心肌损伤，手术或出血性中风，急性镰状细胞危象的商业应用，和许多其他。