Development and Characterization of Triazoloquinazoline derivatives as BMP activators

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