Discovery of glycine sulfonamides as dual inhibitors of sn-1-diacylglycerol lipase α and α/β-hydrolase domain 6.

Abstract

sn-1-Diacylglycerol lipase α (DAGL-α) is the main enzyme responsible for the production of the endocannabinoid 2-arachidonoylglycerol in the central nervous system. Glycine sulfonamides have recently been identified by a high throughput screening campaign as a novel class of inhibitors for this enzyme. Here, we report on the first structure-activity relationship study of glycine sulfonamide inhibitors and their brain membrane proteome-wide selectivity on serine hydrolases with activity-based protein profiling (ABPP). We found that (i) DAGL-α tolerates a variety of biaryl substituents, (ii) the sulfonamide is required for inducing a specific orientation of the 2,2-dimethylchroman substituent, and (iii) a carboxylic acid is essential for its activity. ABPP revealed that the sulfonamide glycine inhibitors have at least three off-targets, including α/β-hydrolase domain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dual DAGL-α/ABHD6 inhibitor, which makes this compound a potential lead for the discovery of new molecular therapies for diet-induced obesity and metabolic syndrome.

• Authors: Freek J Janssen, Hui Deng, Marc P Baggelaar, Marco Allarà, Tom van der Wel, Hans den Dulk, Alessia Ligresti, Annelot C M van Esbroeck, Ross McGuire, Vincenzo Di Marzo, Herman S Overkleeft, Mario van der Stelt
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 15 Pg. 6610-22 (Aug 14 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24988361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• N-((2,2-dimethylchroman-6-yl)sulfonyl)-N-(4-phenoxybenzyl)glycine
• Proteome
• Sulfonamides
• ABHD6 protein, human
• ABHD6 protein, mouse
• Monoacylglycerol Lipases
• Lipoprotein Lipase
• Glycine

Topics

• Animals
• Brain (metabolism)
• Glycine (analogs & derivatives, chemistry, pharmacology)
• HEK293 Cells
• Humans
• Lipoprotein Lipase (antagonists & inhibitors)
• Mice
• Models, Molecular
• Monoacylglycerol Lipases (antagonists & inhibitors)
• Proteome (metabolism)
• Structure-Activity Relationship
• Sulfonamides (chemistry, pharmacology)