A Hybrid Katp Channel Opener to Prevent Radiocontrast-Induced Nephropathy

用于预防放射性对比诱发肾病的混合 Katp 通道开放剂

• 批准号: 8248636
• 负责人: Kanneganti Murthy
• 金额: $ 25.44万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248636
• 关键词: 3-nitrotyrosine; Animal Model; Animals; Antihypertensive Agents; Apoptosis; Atherosclerosis; Attenuated; Biochemical; Biological; Chlorine; Clinical; Complex; Complication; Coronary; Creatinine; Cytoprotection; Defense Mechanisms; Dehydration; Development; Diagnostic; Dialysis procedure; Dose; Elderly; Electron Transport; Engineering; Excision; Exhibits; F2-Isoprostanes; Free Radicals; Functional disorder; Gelatinase A; Generations; Glomerular Filtration Rate; Histologic; Histology; Hybrids; Hydrogen Peroxide; Hyperglycemia; Hypotension; Image; Impairment; In Situ Nick-End Labeling; Incidence; Infarction; Infiltration; Inflammation; Injury; Intravenous; Islet Cell; Isoprostanes; Kidney; Kidney Diseases; Kidney Failure; Lasers; Lead; Lipid Peroxidation; Malondialdehyde; Measurement; Measures; Mediating; Mitochondria; Modality; Modeling; Mus; Myocardial Ischemia; Necrosis; Organ; Oxidation-Reduction; Oxidative Stress; Pancreas; Pathway interactions; Peripheral; Peroxidases; Peroxonitrite; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; Pinacidil; Placebo Control; Poly Adenosine Diphosphate Ribose; Population; Prevention; Procedures; Production; Prostaglandin-Endoperoxide Synthase; Pyrrolidines; Randomized; Rattus; Reactive Oxygen Species; Renal function; Reperfusion Injury; Research Contracts; Risk; Rodent; Rodent Model; Safety; Schedule; Series; Single-Blind Study; Small Business Innovation Research Grant; Sprague-Dawley Rats; Staining method; Stains; Superoxide Dismutase; Superoxides; Testing; Therapeutic; Therapeutic Uses; Tissues; Toxicology; United States National Institutes of Health; Vascular Smooth Muscle; Vasodilator Agents; analog; antioxidant therapy; arteriole; catalase; catalyst; cell injury; clinically relevant; diabetic; healthy volunteer; improved; in vivo; inhibitor/antagonist; innovation; kidney cell; lung injury; mimetics; mitochondrial K(ATP) channel; nephrogenesis; neutrophil; nitrosative stress; novel; pharmacophore; prevent; professor; prophylactic; prospective; pyrrolidine; rat KIM-1 protein; renal ischemia; response; small molecule; tool; urinary

DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is developing a novel K+-ATP channel opener (R-801) for the prevention of radiocontrast media (CM) induced nephropathy (CIN), a devastating complication developing in > 25% of diabetics with significant preexisting renal dysfunction. The high incidence of atherosclerosis in this population frequently necessitates angiographic procedures of the coronary and peripheral vasculature, wherein large quantities of CM are utilized; thus, risk of CIN is a major concern. R-801 is a bifunctional small molecule, formed from the covalent linkage of: 1) the non-selective K+-ATP channel opener pinacidil, and 2) a pyrrolidine nitroxide that acts as a superoxide dismutase mimetic, a catalase mimic, and a peroxynitrite decomposition catalyst. R-801 behaves as a mitochondrial-selective K+-ATP channel opener, providing profound cytoprotection without induction of hyperglycemia and diastolic hypotension. The addition of the redox catalytic function provides R-801 with the capacity to neutralize not only reactive oxygen species generated by CM administration but also the removal of superoxide anion generated by mitoK+-ATP channel mediated inhibition of the first component of the electron transport chain. Taken together, R-801 represents the first agent intended to safely exploit K+-ATP channel activation as a clinical prophylactic for CIN. In support of this approach, in a rodent model of renal ischemia/reperfusion injury R- 801 profoundly reduced the elevation in BUN and creatinine, blocked neutrophil inflammation, and prevented histologic evidence of necrosis. Similar benefits have been observed in other rodent redox models, including myocardial ischemia/reperfusion injury and chlorine inhalational lung injury. We now propose to establish the dose-response of R-801 in a classic model of CIN and to validate its mechanism of action. Aim #1: Establish the pharmacodynamic (PD) profile of R-801 in preventing tissue injury in a rodent model of CIN. Rats will be subjected to dehydration, prostaglandin synthetase inhibition, and an intravenous challenge of CM. A sham injury group will be compared to treatment with R-801, pinacidil, or R-801 given in combination with a mitoK+-ATP channel inhibitor (5-hydroxydecanoate). We expect that R- 801 will exhibit dose-dependent superiority to pinacidil and vehicle control, as shown by: 1) Reduced tissue injury, manifested by the level of tissue necrosis (histology score), lipid peroxidation (malondialdehyde, F21-isoprostane), PMN infiltration (myeloperoxidase), apoptosis (TUNEL staining), 3-nitrotyrosine (a measure of ONOO- formation), poly(ADP-ribose) (a measure of PARP activity); and 2) Improved renal function, reflected by the concentration of urinary Kidney Injury Molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). We expect that the efficacy of R-801 will be attenuated by 5- hydroxydecanoate, demonstrating the centrality of mitoK+-ATP channel activation to its mechanism of cytoprotection. PUBLIC HEALTH RELEVANCE: Radiocontrast imaging is an invaluable and frequently used diagnostic modality, but its use is complicated by the subsequent development of kidney injury, often to the extent of requiring dialysis, particularly in populations at greatest risk, such as th elderly, diabetic, and those with preexisting renal impairment. There are no approved pharmaceutical therapies to prevent this complication. We are developing a novel prophylactic agent that protects the kidney from radiocontrast administration by directly protecting kidney cells from injury. We now propose to test this agent in a clinically-relevant small animal model of radiocontrast-induced kidney failure.

描述（由申请人提供）：Radikal Therapeutics（RTX）正在开发一种新颖的K+-ATP通道开瓶器（R-801），用于预防放射性对比媒体（CM）诱导的肾病（CIN），这是一种损坏的并发症，在> 25％的糖尿病患者中遭受了严重的糖尿病患者，具有重大的糖尿病，具有重大的肾上腺素。该人群中动脉粥样硬化的高发病率通常需要进行冠状动脉和外围脉管系统的血管造影程序，其中使用了大量CM。因此，CIN的风险是一个主要问题。 R-801是一种双功能的小分子，由以下共价链接形成：1）非选择性的K+-ATP通道开瓶器Pinacidil，以及2）吡咯烷硝基氧化物，可作为超氧化物验证酶模拟酶模拟物，一种催化酶模拟于催化酶，催化氧化酶的氧化脱氧化酶，并氧化氧化脱氧于氧化脱氧化酶。 R-801作为线粒体选择性K+-ATP通道开瓶的行为，提供了深刻的细胞保护作用，而无需诱导高血糖和舒张性低血压。氧化还原催化功能的添加提供了R-801的能力，不仅可以中和CM给药产生的活性氧，而且还可以去除MITOK+-ATP通道介导的电子转运链的第一组所产生的超氧化物阴离子。综上所述，R-801代表了第一种旨在安全利用K+-ATP通道激活作为CIN临床预防性的药物。为了支持这种方法，在肾脏缺血/再灌注损伤的啮齿动物模型中，R-801大大降低了BUN和肌酐的升高，阻塞了中性粒细胞炎症，并阻止了坏死的组织学证据。在其他啮齿动物氧化还原模型中也观察到了类似的好处，包括心肌缺血/再灌注损伤和氯吸入肺损伤。现在，我们建议在经典的CIN模型中建立R-801的剂量反应，并验证其作用机理。 AIM＃1：在CIN啮齿动物模型中，建立R-801的药效学（PD）谱。大鼠将受到脱水，前列腺素合成酶抑制和CM的静脉挑战。将MAM损伤组与用MITOK+-ATP通道抑制剂（5-羟基二烷酸盐）结合给出的R-801，Pinacidil或R-801的治疗。 We expect that R- 801 will exhibit dose-dependent superiority to pinacidil and vehicle control, as shown by: 1) Reduced tissue injury, manifested by the level of tissue necrosis (histology score), lipid peroxidation (malondialdehyde, F21-isoprostane), PMN infiltration (myeloperoxidase), apoptosis (TUNEL staining), 3-硝基酪氨酸（一种量度），poly（adp-ribose）（PARP活性的量度）； 2）改善了肾功能，由尿肾损伤分子-1（KIM-1）和中性粒细胞明胶相关的脂肪蛋白（NGAL）反射。我们预计R-801的疗效将被5-羟基二烷酸盐降低，这表明MITOK+-ATP通道激活的中心性对其细胞保护机制。 公共卫生相关性：放射对比度成像是一种宝贵的，常用的诊断方式，但随后的肾脏损伤的发展通常是需要透析的范围，尤其是在最大风险的人群中，例如老年人，糖尿病患者以及患有肾脏危害的肾脏损害的人的使用变得复杂。没有批准的药物疗法可以防止这种并发症。我们正在开发一种新型的预防剂，该预防剂通过直接保护肾细胞免受损伤来保护肾脏免受放射性对比的给药。现在，我们建议在与临床上相关的小动物模型中测试该药物 放射性对称性引起的肾衰竭。