Development and optimization of piperidyl-1,2,3-triazole ureas as selective chemical probes of endocannabinoid biosynthesis.
J Med Chem
; 56(21): 8257-69, 2013 Nov 14.
Article
em En
| MEDLINE
| ID: mdl-24152245
ABSTRACT
We have previously shown that 1,2,3-triazole ureas (1,2,3-TUs) act as versatile class of irreversible serine hydrolase inhibitors that can be tuned to create selective probes for diverse members of this large enzyme class, including diacylglycerol lipase-ß (DAGLß), a principal biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we provide a detailed account of the discovery, synthesis, and structure-activity relationship (SAR) of (2-substituted)-piperidyl-1,2,3-TUs that selectively inactivate DAGLß in living systems. Key to success was the use of activity-based protein profiling (ABPP) with broad-spectrum and tailored activity-based probes to guide our medicinal chemistry efforts. We also describe an expanded repertoire of DAGL-tailored activity-based probes that includes biotinylated and alkyne agents for enzyme enrichment coupled with mass spectrometry-based proteomics and assessment of proteome-wide selectivity. Our findings highlight the broad utility of 1,2,3-TUs for serine hydrolase inhibitor development and their application to create selective probes of endocannabinoid biosynthetic pathways.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Triazóis
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Ureia
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Endocanabinoides
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Inibidores Enzimáticos
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Descoberta de Drogas
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article