A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation

Abstract

Fatty acid ethanolamides such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are lipid-derived mediators that potently inhibit pain and inflammation by ligating type-α peroxisome proliferator-activated receptors (PPAR-α). These bioactive substances are preferentially degraded by the cysteine hydrolase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages. Here we describe a new class of β-lactam derivatives that are potent, selective and systemically active inhibitors of intracellular NAAA activity. The prototype of this class deactivates NAAA by covalently binding the enzyme's catalytic cysteine, and exerts profound anti-inflammatory effects in both mouse models and human macrophages. This agent may be used to probe the functions of NAAA in health and disease and as a starting point to discover better anti-inflammatory drugs.

An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freunds Adjuvant Rat Model of Arthritis

“…6A, CFA injection was accompanied by an increase in NAAA in inflamed paws, as assessed by activity assays, and this effect was significantly reduced by administration of ARN726 (30 mg/kg, i.p.). ARN726 also normalized paw levels of PEA and OEA, which, as expected from previous work (Zhu et al, 2011;Sasso et al, 2013;Ribeiro et al, 2015), were lowered by treatment with CFA (Fig. 6, B and C).…”

“…The cellular localization of this enzyme-which is highly concentrated in macrophages and B-lymphocytes compared with other cell lineages (Tsuboi et al, 2005;Ribeiro et al, 2015)-is suggestive of a role in the regulation of innate immune responses. A small number of pharmacological studies support this idea.…”

“…In macrophages, the modulatory actions of PEA and OEA on the inflammatory process are stopped by the intracellular hydrolysis of these substances, which is catalyzed by the cysteine amidase N-acylethanolamine acid amidase (NAAA) (Tsuboi et al, 2005;Ribeiro et al, 2015). The cellular localization of this enzyme-which is highly concentrated in macrophages and B-lymphocytes compared with other cell lineages (Tsuboi et al, 2005;Ribeiro et al, 2015)-is suggestive of a role in the regulation of innate immune responses.…”

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

“…For instance, the covalent adducts of NAAA-125 were detected by mass spectrometry in mice lungs 139 Notably, compound 125 was disclosed as the first β- More recently, the optimization of the β-lactam moiety or the side chain of carbamate-based β-lactams was carried out. 140 The investigation of structure activity-relationships disclosed that a linear and lipophilic side chain is favorable for NAAA inhibitory capacity, and (S)-configuration is preferred rather than its (R)-isomer.…”

“…Indeed, the β-lactam moiety was predicted to form H-bonds with FAAH, whereas the β-lactam was identified to covalently react with NAAA. 139,141 Hence, the reactive secondary β-lactam function rather than tertiary β-lactam is preferred for NAAA.…”