title: An unprecedented reversible mode of action of β-lactams for the inhibition of human fatty acid amide hydrolase (hFAAH).
abstract: 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, IC(50) = 5.3 nM) revealed that log P values and PSA could be optimized without altering the FAAH inhibition (IC(50) values from 3.65 nM to 70.9 nM).
authors.affiliation: Laboratoire de Chimie Organique et Médicinale, Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur L4.01.02, B-1348 Louvain-La-Neuve, Belgium.
authors.forename: Marion
authors.initials: M
authors.lastname: Feledziak
authors.forename: Catherine
authors.initials: C
authors.lastname: Michaux
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marchand-Brynaert
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D047090:beta-Lactams; D000099252:Fatty Acid Amide Hydrolases