Hsu_2013_J.Med.Chem_56_8257

Reference

Title : Development and optimization of piperidyl-1,2,3-triazole ureas as selective chemical probes of endocannabinoid biosynthesis - Hsu_2013_J.Med.Chem_56_8257
Author(s) : Hsu KL , Tsuboi K , Whitby LR , Speers AE , Pugh H , Inloes J , Cravatt BF
Ref : Journal of Medicinal Chemistry , 56 :8257 , 2013
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-beta (DAGLbeta), 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 DAGLbeta 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.

PubMedSearch : Hsu_2013_J.Med.Chem_56_8257
PubMedID: 24152245
Gene_locus related to this paper: human-DAGLB

Related information

Inhibitor KT172    KT109
Gene_locus KT172    KT109    human-DAGLB
Family KT172    KT109    human-DAGLB    ABHD6-Lip

Citations formats

Hsu KL, Tsuboi K, Whitby LR, Speers AE, Pugh H, Inloes J, Cravatt BF (2013)
Development and optimization of piperidyl-1,2,3-triazole ureas as selective chemical probes of endocannabinoid biosynthesis
Journal of Medicinal Chemistry 56 :8257

Hsu KL, Tsuboi K, Whitby LR, Speers AE, Pugh H, Inloes J, Cravatt BF (2013)
Journal of Medicinal Chemistry 56 :8257