β-lactams derived from a carbapenem chiron are selective inhibitors of human fatty acid amide hydrolase versus human monoacylglycerol lipase

A library of 30 β-lactams has been prepared from (3R,4R)-3-[(R)- 1′-(tbutyldimethylsilyloxy)-ethyl]-4-acetoxy-2-azetidinone, and the corresponding deacetoxy derivative, by sequential N- and O-functionalizations with various ω-alkenoyl and ω-arylalkanoyl chains. All compounds were selective inhibitors of hFAAH versus hMGL, and IC₅₀ values in the nanomolar range (5-14 nM) were recorded for the best representatives. From time-dependent preincubation and rapid dilution studies, and from docking analyses in a homology model of the target enzyme, a reversible mechanism of inhibition of hFAAH is proposed.