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

本应用的主要目的在于系统地进一步开发和更详细地表征光和β -辐照活化（所谓的“笼”）蛋白激酶抑制剂的前药。基于已建立的光制药基础设施和我们第一个申请期的令人兴奋的结果，我们将继续为笼状前药建立一个强大的药物化学平台。我们的方法将涉及合适的支架和激酶抑制剂的光或β -辐照活化的概念。因此，可以开发药物释放控制、抑制剂选择性和疗效优化、减少副作用和有效药理工具的创新应用。通过在生物光学窗口中显示波长的光，特别是通过β -辐射激活笼状前体药物，可以增强组织穿透，从而提供显着的治疗优势。利用我们的知识，它也将有可能在一种新的设计方法的意义上开发笼状抑制剂，以进一步的激酶目标和超越的抑制剂。此外，我们的结果将适用于光化学保护基团，特别是n -杂环。

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.