000K  utf8
1100  $c2022
1500  ger
2050  urn:nbn:de:gbv:8:3-2022-00124-9
3000  Lohmann, Stefan
4000  Development and Characterization of Triazoloquinazoline derivatives as BMP activators$hChristian-Albrechts-Universität zu Kiel  [Lohmann, Stefan]
4000  Entwicklung und Charakterisierung von Triazolchinazolinderivaten als BMP-Aktivatoren$hChristian-Albrechts-Universität zu Kiel  [Lohmann, Stefan]
4030  Kiel$nChristian-Albrechts-Universität zu Kiel
4209  The prevalence of bone associated diseases is constantly increasing in the aging population. Bone morphogenetic protein (BMP)-signaling may be involved in pathophysiological processes and has recently gained attention as an attractive osteoinstructive target. We identified the triazoloquinazoline CGS-15943 as a promising small molecule activator of BMP. This work aims to characterize this compound in a multi-perspective manner. For efficiently analyzing the structure-activity relationship (SAR) of the BMP-amplifying effect a "diversity-oriented" synthesis approach was successfully developed. Besides, the physicochemical characterization of the lead compound was addressed via HPLC methods. In order to improve the aqueous solubility, a prodrug approach was pursued. Additionally, to identify BMP-relevant targets, which potentially confer the amplifying effect, a kinase array was utilized to investigate the impact of CGS-15943 on the human kinome. Subsequently, top kinase candidates were thoroughly characterized. In summary, the SAR-study unraveled fundamental findings about the structural demands and the potential for optimization of the BMP-amplifying effect of CGS-15943. The physicochemical characterization implicated an excellent membrane permeability in vivo and a very low water solubility. For the latter an optimization approach was successfully set up by the development of a prodrug concept. Given the characteristic kinome activity profile, a plausible mechanism confering the amplifying effect on BMP-signaling was deduced. A co-crystal structure of a key target with bound CGS-19543 devised for structure-based lead optimization. The findings presented in this work deliver essential knowledge about the physicochemical features and the potential for optimizing the biological efficacy for biotechnical and, especially, therapeutic use of triazoloquinazolines as BMP-activators in the future.
4950  https://nbn-resolving.org/urn:nbn:de:gbv:8:3-2022-00124-9$xR$3Volltext$534
4961  https://macau.uni-kiel.de/receive/macau_mods_00002511
5051  500
5051  540
5051  610
5550  BMP
5550  BMP-signaling
5550  CGS-15943
5550  Heterocyclic Synthesis
5550  Imidazoquinolines
5550  Physicochemical Characterization
5550  Prodrug Synthesis
5550  SAR study
5550  Small Molecule BMP activators
5550  Target identification
5550  Triazoloquinazolines