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

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.

[1]  D. Piomelli,et al.  Advances in the discovery of N-acylethanolamine acid amidase inhibitors. , 2014, Pharmacological research.

[2]  M. Mor,et al.  3‐Aminoazetidin‐2‐one Derivatives as N‐Acylethanolamine Acid Amidase (NAAA) Inhibitors Suitable for Systemic Administration , 2014, ChemMedChem.

[3]  D. Piomelli,et al.  Peripheral gating of pain signals by endogenous lipid mediators , 2014, Nature Neuroscience.

[4]  D. Centonze,et al.  Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis , 2013, Annals of neurology.

[5]  B. Cravatt,et al.  Chemical Probes of Endocannabinoid Metabolism , 2013, Pharmacological Reviews.

[6]  J. O’Shea,et al.  Back to the future: oral targeted therapy for RA and other autoimmune diseases , 2013, Nature Reviews Rheumatology.

[7]  R. Bertorelli,et al.  Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models , 2013, PAIN®.

[8]  D. Piomelli,et al.  Peroxisome Proliferator-Activated Receptor α Mediates Acute Effects of Palmitoylethanolamide on Sensory Neurons , 2012, The Journal of Neuroscience.

[9]  Jin Fu,et al.  Design and Synthesis of Potent N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA) Inhibitor as Anti-Inflammatory Compounds , 2012, PloS one.

[10]  A. Reggiani,et al.  β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine. , 2012, ACS medicinal chemistry letters.

[11]  S. Cuzzocrea,et al.  Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation , 2009, Proceedings of the National Academy of Sciences.

[12]  E. Mazzon,et al.  PPAR-α Contributes to the Anti-Inflammatory Activity of 17β-Estradiol , 2009, Journal of Pharmacology and Experimental Therapeutics.

[13]  D. Piomelli,et al.  Lipidomic analysis of endocannabinoid metabolism in biological samples. , 2009, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[14]  S. Cuzzocrea,et al.  Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-α Agonist, Modulates Carrageenan-Induced Paw Edema in Mice , 2007, Journal of Pharmacology and Experimental Therapeutics.

[15]  N. Ueda,et al.  Molecular Characterization of N-Acylethanolamine-hydrolyzing Acid Amidase, a Novel Member of the Choloylglycine Hydrolase Family with Structural and Functional Similarity to Acid Ceramidase* , 2005, Journal of Biological Chemistry.

[16]  D. Piomelli,et al.  The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-α Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide , 2005, Molecular Pharmacology.

[17]  N. Ueda,et al.  N-cyclohexanecarbonylpentadecylamine: a selective inhibitor of the acid amidase hydrolysing N-acylethanolamines, as a tool to distinguish acid amidase from fatty acid amide hydrolase. , 2004, The Biochemical journal.

[18]  M. Plotkine,et al.  3-Aminobenzamide reduces brain infarction and neutrophil infiltration after transient focal cerebral ischemia in mice , 2003, Experimental Neurology.

[19]  S. Gaetani,et al.  Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α , 2003, Nature.

[20]  アシュラフ・サエード,et al.  Peroxisome proliferator-activated receptor alpha agonist , 2001 .

[21]  N. Ueda,et al.  Purification and Characterization of an Acid Amidase Selective for N-Palmitoylethanolamine, a Putative Endogenous Anti-inflammatory Substance* , 2001, The Journal of Biological Chemistry.

[22]  W. Wahli,et al.  The PPARα–leukotriene B4 pathway to inflammation control , 1996, Nature.

[23]  S. Cuzzocrea,et al.  Diacerein is a potent and selective inhibitor of palmitoylethanolamide inactivation with analgesic activity in a rat model of acute inflammatory pain. , 2015, Pharmacological research.

[24]  A. Cavalli,et al.  Synthesis and Structure − Activity Relationship (SAR) of 2 ‑ Methyl-4-oxo-3-oxetanylcarbamic Acid Esters, a Class of Potent N ‑ Acylethanolamine Acid Amidase (NAAA) Inhibitors , 2013 .

[25]  김진용,et al.  Peroxisome Proliferator-Activated Receptor Alpha , 2003 .

[26]  D. Postma,et al.  Chronic obstructive pulmonary disease. , 2002, Clinical evidence.

[27]  W. Wahli,et al.  The PPARalpha-leukotriene B4 pathway to inflammation control. , 1996, Nature.

[28]  I. Leodolter.  [Crohn's disease]. , 1967, Wiener Zeitschrift fur innere Medizin und ihre Grenzgebiete.

[29]  G PLACITELLI,et al.  [Ulcerative colitis]. , 1958, La Riforma medica.