Design, Synthesis and Enzyme Assay of Novel Fatty Acid Amide Hydrolase (FAAH) Inhibitors

ABSTRACT: OBJECTIVE To discover novel fatty acid amide hydrolase inhibitors and evaluate their enzymatic activity. METHODS The pharmacophore model was based on the compounds carefully selected from the published literatures. This model was used to screen part of ZINC Nature Products database to get a series of compounds which were used to do a superimposition analysis of the FAAH X-ray crystal structure. Through the virtual screening and the structure-activity analysis of the compouds published in the literatures, the hitting compound structure(2-oxygen-benzo pyran-7-ester) was selected to do the transformation. The acylation and condensation reactions were used to get a series of novel compounds. The enzymatic activity was tested by LC-MS in vitro. RESULTS Compounds (±)-2-(2-Phenoxy-acetylamino)-propionic acid 2-oxo-2H-chromen-7-yl ester(2b)(IC50 95.24 μmol.L-1)and (±)-1-(2-Phenoxy-acetyl)-pyrrolidine-2-carboxylic acid 2-oxo-2H-chromen-7-yl ester (2g)(IC50 17.34 μmol.L-1)showed good inhibition to FAAH in enzyme assay. CONCLUSION The compounds which had been discovered were different from other FAAH inhibitors and worthy of further study as a lead compound.