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

作者：Feledziak Marion; Michaux Catherine; Lambert Didier M; Marchand Brynaert Jacqueline^*

来源：European Journal of Medicinal Chemistry, 2013, 60: 101-111.

DOI：10.1016/j.ejmech.2012.11.035

• beta-Lactam
• Azetidinone
• Reversible inhibition
• Noncovalent inhibition
• Fatty acid amide hydrolase
• Serine hydrolase
• Endocannabinoid system
• Anandamide

A series of compound was prepared to clarify the reversible mechanism of beta-lactamic hFAAH inhibitors on the one hand, and to modulate some of their physicochemical parameters on the other hand. In particular, two compounds (4h 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 beta-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).

• 出版日期2013-2