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3‐Heterocycle‐Phenyl N ‐Alkylcarbamates as FAAH Inhibitors: Design, Synthesis and 3D‐QSAR Studies
Author(s) -
Käsnänen Heikki,
Myllymäki Mikko J.,
Minkkilä Anna,
Kataja Antti O.,
Saario Susanna M.,
Nevalainen Tapio,
Koskinen Ari M. P.,
Poso Antti
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900390
Subject(s) - quantitative structure–activity relationship , fatty acid amide hydrolase , chemistry , in silico , stereochemistry , aryl , alkyl , biochemistry , organic chemistry , agonist , receptor , cannabinoid receptor , gene
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 n M ). 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.