Systematic further development of caged prodrugs of protein kinase inhibitors by UV light and beta-irradiation

本申请的主要目的在于系统地进一步开发和更详细地表征蛋白激酶抑制剂的光和β辐射可激活(所谓的笼式)前药。在已建立的光制药基础设施的基础上，通过我们第一个申请期令人振奋的结果，我们将继续为笼子前药建立一个强大的药物化学平台。我们的方法将包括合适的支架和激酶抑制剂，用于光或通过贝塔辐射激活的概念。因此，可以在控制药物释放、优化抑制剂的选择性和有效性、减少副作用和有效的药理工具方面开发创新的应用。通过在生物光学窗口中显示波长的光，特别是通过贝塔辐射来激活笼形前药，将增强组织穿透，从而提供显着的治疗优势。利用我们的知识，也将有可能开发笼式抑制剂，在某种意义上，从头设计方法，以进一步的激酶靶标和更远的抑制剂。此外，我们的结果将适用于保护基团的光化学，特别是N-杂环的光化学。

The main objectives of the present application consist in a systematic further development and more detailed characterization of photo- and by beta-irrradiation activatable (so-called "caged") prodrugs of protein kinase inhibitors. On the basis of the established photo-pharmaceutical infrastructure and by our exciting results of the first application period we will continue to build a powerful medicinal-chemistry platform for caged prodrugs. Our approach will involve suitable scaffolds and kinase inhibitors for the photo- or by beta-irradiation activatable concept. Innovative applications for the control of drug release, optimization of inhibitor selectivity and efficacy, reduction of side effects and effective pharmacological tools can thus be developed. Activation of caged prodrugs by light showing a wavelength in the bio-optical window and in particular by beta-irradiation would enhance the tissue penetration thus providing significant therapeutic advantages. Using our knowledge it will then also be possible to develop caged inhibitors in the sense of a de novo design approach towards inhibitors of further kinase targets and beyond. Moreover, our results will be applicable to the photochemistry of protecting groups in particular for N-heterocycles.