Chiral disubstituted piperidinyl ureas: a class of dual diacylglycerol lipase-α and ABHD6 inhibitors

Abstract

The enantioselective synthesis and structure–activity relationships of deoxy-iminosugar-based triazole ureas as dual inhibitors of DAGLα and ABHD6 were reported.

ABHD6: Its Place in Endocannabinoid Signaling and Beyond

“…However, the next generation of carbamate-based ABHD6 inhibitors have reached greater potency, selectivity and in vivo activity, including the brain-penetrant compound KT-182, the peripherally-restricted compound KT-203, and the orally-available compound KT-185 [49]. In addition, triazole urea featuring chiral hydroxylated 2-benzylpiperidines have recently been synthesized to act as dual inhibitors of both DGL and ABHD6, citing the chirality of the carbon at the C2 substituent and position of the C5 hydroxyl to dictate inhibitory activity on the enzymes in mouse brain extracts [54]. Finally, the recent chemical biology tools based on fluorescence activity-based probes that are being developed to try and differentiate the enzymatic activity of these enzymes will certainly help develop more select inhibitors [55].…”

Development and biological applications of sulfur–triazole exchange (SuTEx) chemistry

“…The enhanced nucleophilicity of the base-activated catalytic serine makes it highly amenable to covalent modification by electrophilic ABPs and inhibitors. 61 Development of affinity labeling agents 98 led to the discovery of 1,2,3-triazole ureas (1,2,3-TUs) as potent and selective irreversible inhibitors that inactivate SHs through carbamoylation of the catalytic serine 20,88,95,[99][100][101][102][103][104] (Fig. 1).…”

“…Development of affinity labeling agents 98 led to the discovery of 1,2,3-triazole ureas (1,2,3-TUs) as potent and selective irreversible inhibitors that inactivate SHs through carbamoylation of the catalytic serine 20 , 88 , 95 , 99 – 104 ( Fig. 1 ).…”

α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases

“…A series of dual ABHD6 and DAGLα inhibitors were recently published by Deng et al 127 Their strategy aimed at finding dual inhibitors as potential therapeutic agents to treat metabolic and neurodegenerative diseases. This series of dual inhibitors bear the chiral hydroxylated 2-benzylpiperdine scaffold with a triazole urea moiety.…”