Design, synthesis and biological evaluation of naphthyl amide derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.
Bioorg Med Chem
; 111: 117844, 2024 Sep 01.
Article
in En
| MEDLINE
| ID: mdl-39106652
ABSTRACT
Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Design
/
Cell Proliferation
/
Enzyme Inhibitors
/
Amides
/
Monoacylglycerol Lipases
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2024
Document type:
Article
Country of publication:
United kingdom