O‐(Triazolyl)methyl Carbamates as a Novel and Potent Class of Fatty Acid Amide Hydrolase (FAAH) Inhibitors

Abstract

Inhibition of fatty acid amide hydrolase (FAAH) activity is under investigation as a valuable strategy for the treatment of several disorders, including pain and drug addiction. A number of potent FAAH inhibitors belonging to different chemical classes have been disclosed. O-aryl carbamates are one of the most representative families. In the search for novel FAAH inhibitors, we synthesized a series of O-(1,2,3-triazol-4-yl)methyl carbamate derivatives exploiting the copper-catalyzed [3 + 2] cycloaddition reaction between azides and alkynes (click chemistry). We explored structure-activity relationships within this new class of compounds and identified potent inhibitors of both rat and human FAAH with IC50 values in the single-digit nanomolar range.

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…80,81 Since a triazolylmethoxy group acts as a poorer leaving group than phenoxy, such a replacement was deemed to confer higher stability to the molecules. This hypothesis was confirmed by pharmacokinetics studies.…”

“…80 nM, selectivity index (SI) > 1000, Figure 18). 81 The newly introduced alkyloxycarbonyl function at the 3-position of the pyrazole ring was expected to form an H-bond with the hydroxyl group of Thr488, since this latter interaction was previously identified as a means to improve reactivity and selectivity of the molecules toward FAAH.…”

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

“…Carbamates are known to be susceptible to chemical hydrolysis in aqueous solution as well as to enzymatic degradation in biological environments . The chemical stabilities of compounds 32 , 34 , 45 – 47 , 51 , 54 , 59 , and 60 were tested (Table ).…”

A Swath Label-Free Proteomics insight into the Faah−/− Mouse Liver

“…AEA, besides its role in neural generation of pleasure and motivation 4 , has also been shown to inhibit human breast cancer cell proliferation and implantation of embryo in early stages of development 5 – 7 . Given the role of AEA, FAAH has been extensively studied and investigated as potential pharmacological target, and several inhibitors for this enzyme have been developed in the last years 8 , 9 . Very recently, though (2016), a dramatic failure of a clinical trial for safety of a FAAH inhibitor has put a serious question mark on FAAH pharmacology, although subsequent work demonstrated very relevant off-target liabilities 10 of the inhibitor used.…”