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)

• Published in: Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8270-8279
• Main Authors: Hsu, Ku-Lung, Tsuboi, Katsunori, Chang, Jae Won, Whitby, Landon R, Speers, Anna E, Pugh, Holly, Cravatt, Benjamin F
• Format: Article
• Language: English
• Subjects: Animals; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Humans; Mice; Models, Animal; Molecular Structure; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - metabolism; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - metabolism; Triazoles - pharmacology; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400899c

α/β-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 (