Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Abstract

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein-ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)-and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.

Radiosynthesis and Evaluation of [11C-Carbonyl]-Labeled Carbamates as Fatty Acid Amide Hydrolase Radiotracers for Positron Emission Tomography

“…While it is known that both long-chain N -alkyl and N -alkylaryl groups are well tolerated, and bulky alkyl groups are not, 12 there is a paucity of structure–activity information on the FAAH inhibiting activity of heteroatom containing N -alkyl carbamates. In this regard, we found that all three N -piperidinyl O -arylcarbamates ( 9 – 11 ) were impotent as FAAH inhibitors despite differing from known potent FAAH inhibitors only by the inclusion of a tertiary nitrogen in the cyclohexylring (Table 1).…”

Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

“…A solution of p-nitrophenylchloroformate (120 mg, 0.6 mmol) in CH 3 CN (2 mL) was added to a stirred solution of 3-(4,5-dihydrooxazol-2-yl)phenol 46 (100 mg, 0.6 mmol) and DIPEA (110 μL, 0.63 mmol)) in CH 3 CN (2 mL) and DMSO (0.8 mL). The mixture was stirred at ambient temperature for 20 min then quenched with 5% citric acid (17 mL).…”

Discovery and Development of Endocannabinoid-Hydrolyzing Enzyme Inhibitors

“…In addition to the above mentioned carbamates, Myllymäki and Minkkilä et al have described a series of heterocyclic phenyl carbamates (20)(21)(22) as nanomolar FAAH inhibitors ( Table 5) [108][109][110]112]. Interestingly, the parasubstituted compound 21 was also able to inhibit MGL, albeit with a 50 times higher IC 50 value than that of FAAH [108].…”

“…In addition to modification to the N-alkyl moiety, carbamates have been modified by various O-and N-alkyl/aryl groups [103,[105][106][107][108][109][110][111][112] (Fig. 10), of which 6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexylcar-bamic acid 2-fluorophenyl ester (BMS-1, 19c) inhibited FAAH with an IC 50 value of 2 nM ( Table 5) [107].…”