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。需要具有新作用机制的新药来管理这些病症。越来越多的证据表明，心脏缺血（心脏病发作）或脑缺血（中风）会引发一连串激活钙蛋白酶的生化事件。激活的钙蛋白酶降解结构蛋白，导致细胞死亡。因此，钙蛋白酶被认为是心脏病发作和中风干预的有吸引力的药理学靶点。我们已经发现了有效的和选择性的钙蛋白酶抑制剂。考虑到大多数报道的钙蛋白酶抑制剂对酶没有选择性，我们的新抑制剂是令人感兴趣的。然而，我们还没有能够评估的心脏保护作用的抑制剂，因为它们的水溶性差和代谢不稳定的药效醛基。因此，我们建议合成我们的新抑制剂的类似物，其中可氧化的醛基被掩蔽为半缩醛或被不可氧化的官能团如α-酮酰胺和α-酮酰肼取代。这些基团将作为可氧化醛的电子等排药效团替代物并入。我们还将引入可电离基团以提高抑制剂的水溶性。这些变更将允许将抑制剂作为心脏保护剂进行评价。因此，要研究的中心假设是：“我们的新型强效和选择性钙蛋白酶抑制剂的水溶性和代谢稳定衍生物具有心脏保护作用。“具体目标是：（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开发我们的新型钙蛋白酶抑制剂的有效的、选择性的、水溶性的、细胞可渗透的和代谢稳定的类似物;（2）表征将在特定目标#1中使用大鼠离体全脑缺血心脏模型开发的三种最佳抑制剂的心脏保护有效性。这些目标的实现将提供新的钙蛋白酶抑制剂与理想的物理化学性质的生物医学工具，研究钙蛋白酶功能的实验室动物和药物的领导发现新的治疗心脏病发作和中风。此外，拟议的研究将提供机制洞察钙蛋白酶抑制剂作为心脏保护剂的作用模式。