| Title : Discovery of Glycine Sulfonamides as Dual Inhibitors of sn-1-Diacylglycerol Lipase alpha and alpha\/beta-Hydrolase Domain 6 - Janssen_2014_J.Med.Chem_57_6610 |
| Author(s) : Janssen FJ , Deng H , Baggelaar MP , Allara M , van der Wel T , den Dulk H , Ligresti A , van Esbroeck AC , McGuire R , Di Marzo V , Overkleeft HS , van der Stelt M |
| Ref : Journal of Medicinal Chemistry , 57 :6610 , 2014 |
| Abstract : sn-1-Diacylglycerol lipase alpha (DAGL-alpha) 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-alpha 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 alpha/beta-hydrolase domain 6 (ABHD6). Finally, we identified LEI-106 as a potent, dual DAGL-alpha/ABHD6 inhibitor, which makes this compound a potential lead for the discovery of new molecular therapies for diet-induced obesity and metabolic syndrome. |
| ESTHER : Janssen_2014_J.Med.Chem_57_6610 |
| PubMedSearch : Janssen_2014_J.Med.Chem_57_6610 |
| PubMedID: 24988361 |
Janssen FJ, Deng H, Baggelaar MP, Allara M, van der Wel T, den Dulk H, Ligresti A, van Esbroeck AC, McGuire R, Di Marzo V, Overkleeft HS, van der Stelt M (2014)
Discovery of Glycine Sulfonamides as Dual Inhibitors of sn-1-Diacylglycerol Lipase alpha and alpha\/beta-Hydrolase Domain 6
Journal of Medicinal Chemistry
57 :6610
Janssen FJ, Deng H, Baggelaar MP, Allara M, van der Wel T, den Dulk H, Ligresti A, van Esbroeck AC, McGuire R, Di Marzo V, Overkleeft HS, van der Stelt M (2014)
Journal of Medicinal Chemistry
57 :6610