Water-Soluble and Metabolically Stable Calpain Inhibitors as Cardioprotectants

作为心脏保护剂的水溶性且代谢稳定的钙蛋白酶抑制剂

• 批准号: 7073071
• 负责人: Isaac O. Donkor
• 金额: $ 21.9万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073071
• 关键词: calpain; cardiovascular disorder prevention; chemical stability; chemical structure function; chemoprevention; drug design /synthesis /production; drug screening /evaluation; enzyme activity; enzyme inhibitors; hemodynamics; histology; laboratory rat; membrane permeability; myocardial infarction; oxidation; stroke; water solubility

DESCRIPTION (provided by applicant): Our long-term goal is to discover calpain inhibitors as potential treatment for heart attack and stroke. Heart disease and stroke are major causes of mortality and morbidity in the United States. New drugs with novel mechanisms of action are needed for the management of these conditions. Mounting evidence suggests that an episode of cardiac ischemia (heart attack) or cerebral ischemia (stroke) initiates a chain of biochemical events that activate calpain. Activated calpain degrades structural proteins resulting in cell death. Calpain is therefore considered an attractive pharmacologic target for intervention in heart attack and stroke. We have discovered potent and selective inhibitors of calpain. Considering that most of the reported calpain inhibitors are not selective for the enzyme our new inhibitors are of interest. However, we have not been able to evaluate the cardioprotection effect of the inhibitors because of their poor water-solubility and metabolic instability of a pharmacophoric aldehyde group. We are therefore proposing to synthesize analogues of our new inhibitors in which the oxidizable aldehyde group is masked as the hemiacetal or replaced with non-oxidizable functional groups such as the alpha-ketoamide and alpha-ketohydrazide. These groups will be incorporated as isosteric pharmacophoric replacements for the oxidizable aldehyde. We will also incorporate ionizable groups to enhance water solubility of the inhibitors. The changes will allow evaluation of the inhibitors as cardioprotectants. Thus, the central hypothesis to be investigated is: "water-soluble and metabolically stable derivatives of our novel potent and selective calpain inhibitors are cardioprotective." The Specific aims are: (1) to use an iterative approach of structure-based molecular design, synthesis, and enzymological evaluation to develop potent, selective, water-soluble, cell permeable and metabolically stable analogues of our new calpain inhibitors; (2) to characterize the cardioprotection effectiveness of three of the best inhibitors that will be developed in specific aim #1 using the rat isolated heart model of global ischemia. Achievement of these aims will afford new calpain inhibitors with desirable physicochemical properties as biomedical tools for studying calpain function in laboratory animals and as drug leads for the discovery of novel therapies for treating heart attack and stroke. Furthermore, the proposed studies will provide mechanistic insight into the mode of action of calpain inhibitors as cardioprotectants.

描述（由申请人提供）：我们的长期目标是发现钙蛋白酶抑制剂作为心脏病发作和中风的潜在治疗方法。心脏病和中风是美国死亡率和发病率的主要原因。为了管理这些条件，需要具有新型作用机理的新药物。越来越多的证据表明，心脏缺血（心脏病发作）或脑缺血（中风）发起的发作会引发一系列激活钙蛋白酶的生化事件。活性钙蛋白酶降解结构蛋白，导致细胞死亡。因此，Calpain被认为是干预心脏病发作和中风的有吸引力的药理学靶标。我们发现了钙蛋白酶的有效和选择性抑制剂。考虑到大多数报道的钙蛋白酶抑制剂对酶的选择性不是我们的新抑制剂的选择性。但是，我们无法评估抑制剂的心脏保护作用，因为它们的水溶性差和药物醛组的代谢不稳定性。因此，我们提议合成新抑制剂的类似物，其中可氧化的醛基被掩盖为半含量或被α-酮胺和α-酮二酰胺等非氧化官能团取代。这些基团将作为等渗性药理替代物纳入可氧化醛。我们还将结合可离子的组，以增强抑制剂的水溶性。这些变化将允许评估抑制剂作为心脏保护剂。因此，要研究的中心假设是：“我们新型有效和选择性钙蛋白酶抑制剂的水溶性和代谢稳定的衍生物是心脏保护性的。”具体目的是：（1）使用基于结构的分子设计，合成和酶学评估的迭代方法来发展我们新的钙蛋白抑制剂的有效，选择性，水溶性，可渗透和代谢稳定的类似物； （2）表征三种最佳抑制剂的心脏保护有效性，这些抑制剂将在特定的目标＃1中使用大鼠孤立的全球缺血模型在特定的目标＃1中开发。这些目标的实现将为具有理想的物理化学特性提供新的钙蛋白酶抑制剂，作为研究实验动物中钙蛋白酶功能的生物医学工具，并作为药物引导，以发现新的治疗心脏病发作和中风的疗法。此外，拟议的研究将提供有关钙蛋白酶抑制剂作为心脏保护剂的作用方式的机械洞察力。