2014 Jul 2. [Epub ahead of print]
Discovery of Glycine Sulfonamides as Dual Inhibitors of Sn-1 Diacylglycerol Lipase-α and α-β-Hydrolase Domain 6.
Janssen FJ, Deng H, Baggelaar MP, Allarà M, van der Wel T, Dulk HD, Ligresti A, van der Esbroeck AC, McGuire R, Di Marzo V,Overkleeft HS, van der Stelt M.
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 screenings 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.
- PMID:
- 24988361
- [PubMed – as supplied by publisher]
