학술논문
( S)-1-(Pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase ( hFAAH): synthesis, biological evaluation and molecular modelling.
Document Type
Article
Author
Source
Subject
*HYDROXYMETHYL compounds
*AZETIDINE
*CHEMICAL derivatives
*FATTY acids
*AMIDES
*HYDROLASES
*
*
*
*
*
Language
ISSN
1475-6366
Abstract
A series of lipophilic ester derivatives ( 2a- g) of ( S)-1-(pent-4 ′-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from ( S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase ( hFAAH) and monoacylglycerol lipase ( hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the β-lactam core) could be explained on the basis of docking studies into a revisited model of hFAAH active site, considering one or two water molecules in interaction with the catalytic triad. [ABSTRACT FROM AUTHOR]