Discovery of a novel class of profen derivatives as FAAH inhibitors: MD and QM/MM studies of the binding mode and 3D SAR.

SpainFatty acid amide hydrolase (FAAH) is a serine hydrolase that controls the endogenous levels of an importantclass of signalling lipids: the fatty acid ethanolamide family. The best characterized member of this family,anandamide (AEA), is an endogenous ligand for cannabinoid receptors, serves a variety of regulatory functionsin the body and has been implicated in a variety of pathological conditions including pain, inflammation, sleepdisorders, anxiety, depression, and vascular hypertension. This fostered an increasing interest in the developmentof FAAH inhibitors, a promising strategy to regulate endogenous AEA levels. Different classes of FAAHinhibitors have been reported including covalent inhibitors, tight binders and reversible competitive inhibitors.These compounds have been shown to be efficacious in many different pain models, with the advantage oflacking of central effects characteristic of cannabinoid receptor agonists [1-3]. We have recently reported thestudies on the binding mode of the enantiomer forms of Flu-AM1 and Ibu-AM5 [4]. On the basis of these studieswe designed a novel class of profen derivatives bearing a trifluoromethylaminopyridine moiety. Here we reportthe synthesis, pharmacological characterization and computational studies including molecular dynamics andquantum mechanic/ molecular mechanics studies of the binding mode of the lead compound TPA5.