Early-Stage Preclinical Validation of Carbon Monoxide Prodrugs for Acute Kidney Injury

根据PAR-19-294（感兴趣疾病治疗药物的早期临床前验证， NIDDK），我们建议进行一氧化碳（CO）作为治疗药物的临床前验证， 治疗急性肾损伤（阿基），这使大量患者患有严重的，有时是致命的 后果目前，除了维持治疗外，没有其他治疗选择。因此，我们认为， 开发针对阿基的疾病改善治疗将解决重要的、未满足的医疗需求。拟议 开发基于CO的疗法的工作是基于CO的内源性信号传导作用， 大量的文献证据表明CO的细胞和器官保护作用，我们独特的化学工作 通过创新的前药设计将“CO包装在药丸中”，以便于通过药学上可接受的药物递送， 形式，以及我们自己在证明这种CO的器官保护作用方面的广泛初步结果 前药在肾缺血再灌注损伤和横纹肌溶解损伤，肝损伤， 全身性炎症和胃肠道炎症如结肠和胃等。在本申请中， 我们建议研究一些关键的临床前验证问题，并旨在生产一种或多种先导化合物 在资助期结束前准备好进行IND赋能工作。一个非常重要的方面是我们计划使用多个 动物模型包括在猪等大型动物中进行药理学检查 评估，这应该在转化为人类时增加成功的机会。我们特别 建议追求以下具体目标：（1）CO前药的设计、合成和评估，（2） 阿基小鼠模型中CO前药功效的治疗验证，和（3）CO前药的治疗验证 阿基猪模型中的前药。这项拟议中的工作将弥合我们的长期发展目标与发展目标之间的差距。 基于CO的治疗方法和临床前评估的必要性。项目完成后，我们将 开发并充分验证了一系列创新CO前药的功效，这些前药可以提供CO 全身性或选择性靶向肾脏并允许肾脏富集。此外，我们还将开发 后备候选人的管道总的来说，拟议的工作将是发展基于CO的 治疗阿基和其他形式的器官损伤。

In response to PAR-19-294 (Early-Stage Preclinical Validation of Therapeutic Leads for Diseases of Interest to the NIDDK), we propose to conduct preclinical validation of carbon monoxide (CO) as a therapeutic agent for treating acute kidney injury (AKI), which afflicts a large number of patients with serious and sometimes fatal consequences. Currently, there are no treatment options available other than maintenance therapy. Therefore, developing disease modifying treatment for AKI will address an important, unmet medical need. The proposed work of developing CO-based therapeutics is based on CO’s endogenous signaling roles, the availability of a large amount of literature evidence to show CO’s cyto- and organ-protective effects, our unique chemistry work to pack “CO in a pill” through innovative prodrug design for easy delivery through pharmaceutically acceptable forms, and our own extensive preliminary results in demonstrating the organ-protective effects of such CO prodrugs in animal models of kidney ischemia reperfusion injury and rhabdomyolysis injuries, liver injury, systemic inflammation, and GI inflammation such as the colon and stomach, among others. In this application, we propose to examine some key preclinical validation issues and aim to produce one or more lead compounds ready for IND-enabling work by the end of the grant period. A very important aspect is our plan to use multiple animal models including the examination in large animals such as pig to conduct the pharmacological assessment, which should give enhanced chance of success when translating into human. Specifically, we propose to pursue the following specific aims (1) design, synthesis, and assessment of CO prodrugs, (2) therapeutic validation of CO prodrug efficacy in mouse models of AKI, and (3) therapeutic validation of CO prodrugs in pig models of AKI. The proposed work will bridge the gap between our long-term goal of developing CO-based therapeutics and the need for preclinical assessments. Upon completion of the project, we will have developed and fully validated the efficacy of a series of innovative CO prodrugs that can either deliver CO systemically or selectively target the kidney and allow for renal enrichment. Further, we will also have developed a pipeline for backup candidates. Collectively, the proposed work will be a major step in developing CO-based therapeutics against AKI and other forms of organ injury.