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和中风的潜在治疗方法。心脏病和中风是美国死亡和发病的主要原因。治疗这些病症需要具有新颖作用机制的新药。越来越多的证据表明，心脏缺血（心脏病发作）或脑缺血（中风）的发作会引发一系列激活钙蛋白酶的生化事件。激活的钙蛋白酶会降解结构蛋白，导致细胞死亡。因此，钙蛋白酶被认为是干预心脏病和中风的有吸引力的药理学靶点。我们发现了强效且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该酶不具有选择性，我们的新抑制剂引起了人们的兴趣。然而，由于这些抑制剂的水溶性差和药效醛基的代谢不稳定，我们无法评估其心脏保护作用。因此，我们建议合成新抑制剂的类似物，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（例如α-酮酰胺和α-酮酰肼）取代。这些基团将作为可氧化醛的等排药效基团替代物被纳入。我们还将加入可电离基团以增强抑制剂的水溶性。这些变化将允许对抑制剂作为心脏保护剂进行评估。因此，要研究的中心假设是：“我们的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、选择性、水溶性、细胞渗透性和代谢稳定的类似物； (2) 表征将在特定目标#1中使用大鼠离体整体缺血心脏模型开发的三种最佳抑制剂的心脏保护效果。这些目标的实现将提供具有理想理化性质的新型钙蛋白酶抑制剂，作为研究实验动物钙蛋白酶功能的生物医学工具，并作为发现治疗心脏病和中风的新疗法的先导药物。此外，拟议的研究将为钙蛋白酶抑制剂作为心脏保护剂的作用模式提供机制见解。