A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probesThe authors declare no competing interest.Electronic supplementary information (ESI) available: Experimental procedures and analytical data for compounds 9 and 10, in vitro LRRK2 inhibition assays, inhibition mechanism and kinase panel data. See DOI: 10.1039/c5md00462d
Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologicall...
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Main Authors | , , , , , , , , , |
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Format | Journal Article |
Published |
16.03.2016
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Online Access | Get full text |
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Summary: | Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologically relevant space around their key pharmacophore fragment. The combination of organo/metal catalysis and microwave-assisted technology, allowed us to quickly generate highly functionalized heteroaryl-hydrazone derivatives for biological investigation. Enzymatic studies on the synthesized compounds allowed the identification of promising compounds endowed with a good LRRK2 specificity index (wt/G2019S activity ratio), low affinity towards a small panel of selected kinases and a mixed-type inhibition against the pathogenic G2019S mutant. These results show how a diversity-oriented approach based on a privileged pharmacophore fragment may play a key role in the identification of novel biologically relevant chemical probes.
Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. |
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Bibliography: | 10.1039/c5md00462d and in vitro 9 , The authors declare no competing interest. Electronic supplementary information (ESI) available: Experimental procedures and analytical data for compounds LRRK2 inhibition assays, inhibition mechanism and kinase panel data. See DOI 10 |
ISSN: | 2040-2503 2040-2511 |
DOI: | 10.1039/c5md00462d |