A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting 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. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologicall...
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Veröffentlicht in: | MedChemComm 2016-03, Vol.7 (3), p.484-494 |
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Hauptverfasser: | , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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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ISSN: | 2040-2503 2040-2511 |
DOI: | 10.1039/c5md00462d |