Spirocyclic scaffolds as fatty acid mimetics to improve solubility, bioavailability and selectivity

螺环支架作为脂肪酸模拟物，可提高溶解度、生物利用度和选择性

• 批准号: 448583558
• 负责人: Professor Dr. Eugen Proschak
• 金额: --
• 依托单位: Institut für Pharmazeutische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/448583558?language=en
• 关键词: Spirocyclic; scaffolds; fatty; acid; mimetics

Endogenous fatty acid derivatives are involved in various physiological and pathophysiological processes in the context of metabolism and inflammation. Therefore, small molecules which are mimicking or antagonizing these effects, so-called fatty acid mimetics, are of special interest for drug discovery and development. In general, fatty acid mimetics exhibit favorable thermodynamic behavior and pharmacokinetic properties. However, the lipophilic nature of fatty acid mimetics complicates the optimization of solubility, bioavailability and selectivity. In this project, the use of spirocyclic scaffolds in the field of fatty acid mimetics shall be systematically investigated. For this purpose, scaffolds of lead structures for various targets of fatty acid mimetics will be replaced by their spirocyclic counterparts. The resulting lead pairs will be compared in terms of binding affinity, thermodynamics of binding, solubility, in vitro metabolic stability, in vitro bioavailability, and selectivity. The results will clarify whether spirocyclic cores are superior scaffolds in design and synthesis of fatty acid mimetics.

内源性脂肪酸衍生物参与代谢和炎症背景下的各种生理和病理生理过程。因此，模拟或拮抗这些作用的小分子，即所谓的脂肪酸模拟物，对于药物发现和开发具有特别的意义。通常，脂肪酸模拟物表现出有利的热力学行为和药代动力学性质。然而，脂肪酸模拟物的亲脂性使溶解度、生物利用度和选择性的优化复杂化。本项目将系统研究螺环支架在脂肪酸模拟物领域的应用。为此，脂肪酸模拟物的各种靶标的先导结构的支架将被其螺环对应物取代。将在结合亲和力、结合热力学、溶解度、体外代谢稳定性、体外生物利用度和选择性方面比较所得的铅对。这些结果将阐明螺环核在脂肪酸模拟物的设计和合成中是否是上级支架。