An unprecedented reversible mode of action of β-lactams for the inhibition of human fatty acid amide hydrolase (hFAAH)

A series of compound was prepared to clarify the reversible mechanism of β-lactamic hFAAH inhibitors on the one hand, and to modulate some of their physicochemical parameters on the other hand. In particular, two compounds (4b and 4e) were designed to display a potential good leaving group on the crucial carbonyl with a view to possibly acylating the active serine of the hFAAH catalytic triad. Reversibility studies showed that these two compounds retain the reversible mode of inhibition, suggesting a noncovalent interaction between our β-lactams and hFAAH. Finally, pharmacological evaluations of bioisosteres of the lead compound (4a, IC50 = 5.3 nM) revealed that log P values and PSA could be optimized without altering the FAAH inhibition (IC50 values from 3.65 nM to 70.9 nM). [Display omitted] ► Syntheses of new β-lactamic compounds are reported. ► Inhibitory activity is assessed against human fatty acid amide hydrolase (hFAAH). ► Mechanistic studies on compounds 4e and 4b were performed. ► A reversible and noncovalent inhibition on hFAAH is suggested.