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

内源性脂肪酸衍生物在新陈代谢和炎症的背景下参与各种生理和病理生理过程。因此，模拟或拮抗这些效应的小分子，即所谓的脂肪酸模拟物，对药物的发现和开发具有特殊的意义。总的来说，脂肪酸模拟物表现出良好的热力学行为和药代动力学特性。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变得复杂。在本项目中，将系统地研究螺环支架在脂肪酸模拟物领域中的应用。为此，各种脂肪酸模拟靶标的铅结构支架将被它们的螺环对应物所取代。将从结合亲和力、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等方面对所得铅对进行比较。这一结果将阐明螺环核心是否是设计和合成脂肪酸模拟物的优良支架。

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.