Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

Abstract

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC 50 ) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.

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

“…None of the tested compounds showed significant activity against MGL at 100 mM compound concentration, and therefore IC 50 values were not determined. As we found in our earlier work, in phenyl carbamates inhibiting MGL, para-substitution is more favorable than metasubstitution [32]. The stereochemistry of the compounds is illustrated in Fig.…”

“…Additionally compound 3a, which only contained the unsubstituted 2-oxazoline ring, showed good inhibitory activity against FAAH with an IC 50 value of 33 nM. We found earlier [32] that the cyclopentyl derivative 1b (IC 50 ¼ 28 nM) was more active than the npropyl derivative 1a (IC 50 ¼ 109 nM). Similar enhancement in activity was observed for compound 3b in comparison to 3a.…”

“…1) reported in our previous study [32]. Compounds 1a-c inhibit FAAH with IC 50 values of 109, 28 and 47 nM, respectively.…”

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

“…para-substitution is more favourable to the MGL inhibitory activities) [22], meta-and ortho-analogues of 8 and its most potent derivative with N-dodecyl group (26) were prepared and tested (Table 6).…”

“…Therefore, several FAAH inhibitors have been developed (see for review Ref. [12]), including various fatty acid derivatives [13][14][15][16][17], and non-lipid inhibitors such as a-keto heterocycles [18][19][20], carbamate derivatives [21][22][23][24][25], (thio)-hydantoins [26] and most recently, selective piperidine/piperazine ureas [27,28]. Probably, the most well-studied FAAH inhibitors are the carbamate-based 3 0 -carbamoylbiphenyl-3-yl ester (4, URB597) ( Fig.…”