3-Heterocycle-phenyl N-alkylcarbamates as FAAH inhibitors: design, synthesis and 3D-QSAR studies.
Carbamates are a well-established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta-substituted phenolic N-alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3-(oxazol-2yl)phenyl cyclohexylcarbamate (2 a), inhibited FAAH with a sub-nanomolar IC(50) value (IC(50)=0.74 nM). Additionally, we developed and validated three-dimensional quantitative structure-activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D-QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D-QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R(2) (PRED)) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.
Käsnänen
Heikki
H
Department of Pharmaceutical Chemistry, University of Kuopio, P.O.Box 1627, 70211 Kuopio, Finland.
Myllymäki
Mikko J
MJ
Minkkilä
Anna
A
Kataja
Antti O
AO
Saario
Susanna M
SM
Nevalainen
Tapio
T
Koskinen
Ari M P
AM
Poso
Antti
A
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016014:Linear Models; D008297:Male; D051379:Mice; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D002219:Carbamates; D004791:Enzyme Inhibitors; D000099252:Fatty Acid Amide Hydrolases