Development and characterization of endocannabinoid hydrolases FAAH and MAGL inhibitors bearing a benzotriazol-1-yl carboxamide scaffold

A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl)methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compou...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2012-11, Vol.20 (21), p.6260-6275
Hauptverfasser:	Morera, Ludovica, Labar, Geoffray, Ortar, Giorgio, Lambert, Didier M.
Format:	Artikel
Sprache:	eng
Schlagworte:	active sites acylglycerol lipase Amidohydrolases - antagonists & inhibitors Amidohydrolases - metabolism Biological and medical sciences Dose-Response Relationship, Drug Drug addictions Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology FAAH FAAH and MAGL inhibitors Fatty acid amide hydrolase fatty acids Humans inhibitory concentration 50 MAGL Medical sciences Models, Molecular Molecular Structure Monoacylglycerol lipase Monoacylglycerol Lipases - antagonists & inhibitors Monoacylglycerol Lipases - metabolism Pharmacology. Drug treatments Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Structure-Activity Relationship structure-activity relationships Toxicology Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology
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Zusammenfassung:	A series of (1H-benzo[d][1,2,3]triazol-1-yl)(4-benzylpiperazin-1-yl)methanones and of (1H-benzo[d][1,2,3]triazol-1-yl)(4-phenylpiperazin-1-yl)methanones has been prepared and tested on human fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In the benzylpiperazinyl series, compound 29 (ML30) exhibited an IC50 value of 0.54nM on MAGL, combined with a 1000-fold selectivity versus FAAH, while compounds 11 and 16 acted as potent dual FAAH-MAGL inhibitors (IC50
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2012.09.011