A Hybrid Katp Channel Opener to Prevent Radiocontrast-Induced Nephropathy

描述（由申请人提供）：Radikal Therapeutics （RTX）正在开发一种新型的K+-ATP通道打开剂（R-801），用于预防造影剂（CM）诱导的肾病（CIN），这是一种发生在bbb25 %的糖尿病患者中具有严重肾功能障碍的毁灭性并发症。在这一人群中，动脉粥样硬化的高发病率经常需要冠状动脉和周围血管的血管造影，其中使用了大量的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，由以下共价键形成：1)非选择性K+-ATP通道开启剂pinacidil， 2)吡咯烷类氮氧化物，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作为线粒体选择性K+-ATP通道开启剂，在不诱导高血糖和舒张性低血压的情况下提供深刻的细胞保护。氧化还原催化功能的加入使R-801不仅具有中和CM给药产生的活性氧的能力，而且还具有去除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的能力。综上所述，R-801代表了第一个旨在安全地利用K+-ATP通道激活作为CIN临床预防的药物。在啮齿动物肾缺血再灌注损伤模型中，R- 801能显著降低BUN和肌酐的升高，阻断中性粒细胞炎症，并阻止组织学上坏死的证据。在其他啮齿类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。我们建议在经典CIN模型中建立R-801的剂量效应，并验证其作用机制。目的1：建立R-801在啮齿动物CIN模型中预防组织损伤的药效学（PD）谱。大鼠将遭受脱水、前列腺素合成酶抑制和静脉注射CM。将假损伤组与R-801、pinacidil或R-801联合mitoK+-ATP通道抑制剂（5-羟乙酸酯）治疗组进行比较。我们预计R- 801将表现出与pinacidil和载体对照相比的剂量依赖性优势，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）、PMN浸润（髓过氧化物酶）、细胞凋亡（TUNEL染色）、3-硝基酪氨酸（一种测量ONOO-形成的方法）、聚（adp -核糖）（一种测量PARP活性的方法）；2)肾功能改善，反映在尿肾损伤分子-1 （KIM-1）和中性粒细胞明胶酶相关脂钙蛋白（NGAL）的浓度上。我们预计R-801的功效会被5-羟癸酸酯削弱，这表明mitoK+- atp通道激活在其细胞保护机制中的中心地位。

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.