63831-39-0Relevant articles and documents
Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors
Patel, Jayendra Z.,Nevalainen, Tapio J.,Savinainen, Juha R.,Adams, Yahaya,Laitinen, Tuomo,Runyon, Robert S.,Vaara, Miia,Ahenkorah, Stephen,Kaczor, Agnieszka A.,Navia-Paldanius, Dina,Gynther, Mikko,Aaltonen, Niina,Joharapurkar, Amit A.,Jain, Mukul R.,Haka, Abigail S.,Maxfield, Frederick R.,Laitinen, Jarmo T.,Parkkari, Teija
, p. 253 - 265 (2015)
At present, inhibitors of α/β-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 = 44 nM) and showed ～ 230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.
