A Hybrid Katp Channel Opener to Prevent Radiocontrast-Induced Nephropathy

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），用于预防放射性造影剂（CM）诱导的肾病（CIN），这是一种毁灭性的并发症，发生在> 25%的既存肾功能不全的糖尿病患者中。该人群中动脉粥样硬化的高发病率经常需要冠状动脉和外周血管的血管造影术，其中使用了大量CM;因此，CIN的风险是一个主要问题。R-801是一种双功能小分子，由以下物质的共价键合形成：1）非选择性K+-ATP通道开放剂吡那地尔，和2）吡咯烷氮氧化物，作为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是一种脑血管选择性K+-ATP通道开放剂，提供了深刻的细胞保护作用，而不会诱导高血糖和舒张期低血压。氧化还原催化功能的增加使R-801不仅能够中和CM给药产生的活性氧，而且能够清除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。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临床预防药物的药物。为了支持这种方法，在肾缺血/再灌注损伤的啮齿动物模型中，R- 801显著降低了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CIN的经典模型中建立R-801的剂量反应，并验证其作用机制。目的#1：在CIN啮齿动物模型中确定R-801预防组织损伤的药效学（PD）特征。将对大鼠进行脱水、前列腺素合成酶抑制和CM静脉内激发。将假损伤组与用R-801、吡那地尔或R-801与mitoK+-ATP通道抑制剂（5-羟基癸酸酯）组合给予的治疗进行比较。我们预计R- 801将表现出剂量依赖性优效于吡那地尔和溶剂对照，如以下所示：1）减少组织损伤，表现为组织坏死水平（组织学评分），脂质过氧化（丙二醛，F21-异前列腺素），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活动的量度）;和2）改善的肾功能，通过尿肾损伤分子-1（KIM-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的浓度反映。我们预计R-801的疗效将被5-羟基癸酸减弱，证明mitoK+-ATP通道激活对其细胞保护机制的中心作用。 公共卫生相关性：放射性造影成像是一种非常宝贵且经常使用的诊断方式，但其使用因随后发生肾损伤而变得复杂，通常达到需要透析的程度，特别是在风险最大的人群中，如老年人、糖尿病患者和既存肾损伤患者。目前还没有批准的药物治疗来预防这种并发症。我们正在开发一种新的预防剂，通过直接保护肾细胞免受损伤来保护肾脏免受放射造影剂给药的影响。我们现在建议在临床相关的小动物模型中测试这种药剂， 放射造影剂导致的肾衰竭

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.