期刊
CHEMMEDCHEM
卷 -, 期 -, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100406
关键词
-
资金
- US National Institutes of Health (NIH) [R01 DA03801]
Fine-tuning 2-arachidonoylglycerol (2-AG) metabolism in the brain through inhibition of a/b-hydrolase domain containing 6 (ABHD6) shows promise in the treatment of epilepsy, neuropathic pain, and inflammation. ABHD6 inhibitors may also have implications in Type-2 diabetes, metabolic syndrome, and other diseases in the periphery.
Fine-tuning than complete disruption of 2-arachidonoylglycerol (2-AG) metabolism in the brain represents a promising pharmacological approach to limit potential untoward effects associated with complete blockade of monoacylglycerol lipase (MGL), the primary hydrolase of 2-AG. This could be achieved through a/b-hydrolase domain containing 6 (ABHD6) inhibition, which will provide a smaller and safer contribution to 2-AG regulation in the brain. Pharmacological studies with ABHD6 inhibitors have recently been reported, where modulation of ABHD6 activity either through CB1R-dependent or CB1R-independent processes showed promise in preclinical models of epilepsy, neuropathic pain and inflammation. Furthermore in the periphery, ABHD6 modulates 2-AG and other fatty acid monoacylglycerols (MAGs) and is implicated in Type-2 diabetes, metabolic syndrome and potentially other diseases. Herein, we report the discovery of single-digit nanomolar potent and highly specific ABHD6 inhibitors with > 1000-fold selectivity against MGL and FAAH. The new ABHD6 inhibitors provide early leads to develop therapeutics for neuroprotection and the treatment of inflammation and diabetes.
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