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) 正在开发一种新型 K+-ATP 通道开放剂 (R-801)，用于预防放射性对比介质 (CM) 诱发的肾病 (CIN)，这是一种破坏性并发症，发生于 > 25% 的肾病患者中。患有严重肾功能不全的糖尿病患者。该人群中动脉粥样硬化的高发病率经常需要对冠状动脉和外周脉管系统进行血管造影手术，其中使用大量的 CM；因此，CIN 的风险是一个主要问题。 R-801 是一种双功能小分子，由以下物质共价连接而成：1) 非选择性 K+-ATP 通道开放剂吡那地尔，以及 2) 吡咯烷氮氧化物，可充当超氧化物歧化酶模拟物、过氧化氢酶模拟物和过氧亚硝酸盐分解催化剂。 R-801 充当线粒体选择性 K+-ATP 通道开放剂，提供深刻的细胞保护作用，而不诱导高血糖和舒张期低血压。氧化还原催化功能的添加使 R-801 不仅能够中和 CM 给药产生的活性氧，还能去除 mitoK+-ATP 通道介导的电子传递链第一组分抑制产生的超氧阴离子。总而言之，R-801 代表了第一种旨在安全地利用 K+-ATP 通道激活作为 CIN 临床预防剂的药物。为了支持这一方法，在肾缺血/再灌注损伤的啮齿动物模型中，R-801 显着降低了 BUN 和肌酐的升高，阻断了中性粒细胞炎症，并防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益处，包括心肌缺血/再灌注损伤和氯吸入性肺损伤。我们现在建议在经典的 CIN 模型中建立 R-801 的剂量反应并验证其作用机制。目标#1：建立 R-801 在 CIN 啮齿动物模型中预防组织损伤的药效 (PD) 曲线。大鼠将遭受脱水、前列腺素合成酶抑制和静脉注射 CM 攻击。将假损伤组与 R-801、吡那地尔或 R-801 联合 mitoK+-ATP 通道抑制剂（5-羟基癸酸酯）的治疗进行比较。我们预计 R-801 将表现出相对于吡那地尔和溶媒对照的剂量依赖性优越性，如下所示： 1) 减少组织损伤，表现为组织坏死（组织学评分）、脂质过氧化（丙二醛、F21-异前列腺素）的水平， PMN 浸润（髓过氧化物酶）、细胞凋亡（TUNEL 染色）、3-硝基酪氨酸（ONOO- 形成的测量）、聚（ADP-核糖）（PARP 活性的衡量标准）； 2) 肾功能改善，反映为尿肾损伤分子 1 (KIM-1) 和中性粒细胞明胶酶相关脂质运载蛋白 (NGAL) 的浓度。我们预计 R-801 的功效会被 5-羟基癸酸酯减弱，这证明了 mitoK+-ATP 通道激活对其细胞保护机制的中心作用。 公众健康相关性：放射性对比成像是一种非常宝贵且经常使用的诊断方式，但其使用因肾损伤的后续发展而变得复杂，通常达到需要透析的程度，特别是在高危人群中，例如老年人、糖尿病患者、以及那些先前存在肾功能不全的人。没有批准的药物疗法可以预防这种并发症。我们正在开发一种新型预防剂，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剂的影响。我们现在建议在临床相关的小动物模型中测试这种药物 放射性对比剂引起的肾衰竭。