beta-Lactams derived from a carbapenem chiron are selective inhibitors of human fatty acid amide hydrolase versus human monoacylglycerol lipase.
A library of 30 beta-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 omega-alkenoyl and omega-arylalkanoyl chains. All compounds were selective inhibitors of hFAAH versus hMGL, and IC(50) 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.
Feledziak
Marion
M
Unite de Chimie Organique et Medicinale, Universite Catholique de Louvain, Batiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-La-Neuve, Belgium.
Michaux
Catherine
C
Urbach
Allan
A
Labar
Geoffray
G
Muccioli
Giulio G
GG
Lambert
Didier M
DM
Marchand-Brynaert
Jacqueline
J
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015780:Carbapenems / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D015780:Carbapenems; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases