Discovery and optimization of piperidyl-1,2,3-triazole ureas as potent, selective, and in vivo-active inhibitors of α/β-hydrolase domain containing 6 (ABHD6)
| Autor: | Landon R. Whitby, Katsunori Tsuboi, Holly Pugh, Anna E Speers, Jae Won Chang, Ku-Lung Hsu, Benjamin F. Cravatt |
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| Rok vydání: | 2013 |
| Předmět: |
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2 3-Triazole Stereochemistry medicine.medical_treatment Article Serine chemistry.chemical_compound Mice Structure-Activity Relationship Piperidines In vivo Hydrolase Drug Discovery medicine Animals Humans Urea Enzyme Inhibitors Dose-Response Relationship Drug Molecular Structure Chemistry Serine hydrolase Triazoles ABHD6 Transmembrane protein Monoacylglycerol Lipases Biochemistry Models Animal Molecular Medicine Cannabinoid |
| Zdroj: | Journal of medicinal chemistry. 56(21) |
| ISSN: | 1520-4804 |
| Popis: | Alpha/beta-hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells (< 5 nM) and, at equivalent doses in mice (1 mg kg-1), served as systemic and peripherally-restricted ABHD6 inhibitors, respectively. We also describe an orally-bioavailable ABHD6 inhibitor KT185 that displays excellent selectivity against other brain and liver serine hydrolases in vivo. We thus describe several chemical probes for biological studies of ABHD6, including brain-penetrant and peripherally-restricted inhibitors that should prove of value for interrogating ABHD6 function in animal models. |
| Databáze: | OpenAIRE |
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