Discovery of Boronic Acids as Novel and Potent Inhibitors of Fatty Acid Amide Hydrolase

Abstract

A series of commercial phenyl-, heteroaryl-, alkyl-, and alkenylboronic acids were evaluated for their FAAH and MGL inhibitory activities. The compounds were generally selective for FAAH, with IC50 in the nanomolar or low-micromolar range. Eight of these compounds inhibited MGL with IC50 in the micromolar range. The most potent compound, phenylboronic acid with para-nonyl substituent (13), inhibited FAAH and MGL with IC50 of 0.0091 and 7.9 microM, respectively.

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

“…108 In 2008, boronic acids were determined to inhibit FAAH. 109 The para-substituted hydrophobic or electron-withdrawing groups of phenylboronic acids were shown to be advantageous for the inhibitory activity against FAAH. Notably, (4-nonylphenyl) boronic acid 75 (Figure 31a) exerted potent FAAH inhibitory capacity (IC50 (rFAAH) = 9.1 nM).…”

“…109 The covalent interaction between 75 and Ser241 was presumed to form a reversible tetrahedral intermediate (Figure 31b). 109 According to recent research on molecular binding simulation of FAAH, 30,34 it was hypothesized that 4-nonylphenyl might be located in the ABP. Although the binding mechanism between boronic acid-based inhibitors and FAAH is still not clear, the remarkable inhibitory efficacy makes boronic acids useful chemical tools to further elucidate the catalytic mechanism of FAAH.…”

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

“…Inhibition by N-alkylcarbamates is based on irreversible acylation of the active site serine [25]. Recently reported other structure families with inhibitory activity against FAAH include (thio)hydantoins [26], piperidine-and piperazine ureas [27,28], sulfonyl derivatives [29] and boronic acid derivatives [30].…”

Inactivation and Biotransformation of the Endogenous Cannabinoids Anandamide and 2-Arachidonoylglycerol

“…However, the development of MAGL inhibitors has lagged historically. Evidence suggests that boronic acids potently inhibit FAAH and may serve as good starting compounds for the development of better MAGL inhibitors (Minkkilä et al, 2008). Long and colleagues (2009) announced their development of a selective MAGL inhibitor, JZL184, that produces antinociceptive effects, hypomotility, and hypothermia in mice (Long et al, 2009).…”