Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-α Agonist, Modulates Carrageenan-Induced Paw Edema in Mice

D’Agostino, Giuseppe; Rana, Giovanna La; Russo, Roberto; Sasso, Oscar; Iacono, A; Esposito, Emanuela; Raso, Giuseppina Mattace; Cuzzocrea, Salvatore; Verme, Jesse Lo; Piomelli, Daniele; Meli, Rosaria; Calignano, Antonio

doi:10.1124/jpet.107.123265

Cited by 133 publications

(116 citation statements)

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“…First, alcohols 5 were converted into the corresponding chloroformates (6), imidazole 1-carboxylates (7), or 2-pyridyl carbonates (8) and 2-oxopyridine-1-carboxylates (9). Then, compounds 6−9 were reacted either with (2S,3R)-2-methyl-4-oxo-3-oxetanylammonium toluene-4-sulfonate (13) to give the desired final compounds (path A) or with the commercially available threonines 10a−d (path B) to furnish the intermediate α-substituted-β-hydroxycarboxylic acids 15a−h,j,k,n,o,r and 16− 18, which upon cyclization afforded the corresponding 2-methyl-4-oxo-3-oxetanylcarbamic acid esters.…”

Section: ■ Chemistrymentioning

confidence: 99%

“…3−6 The pharmacology of PEA has been extensively investigated. 7 The compound inhibits peripheral inflammation and mast cell degranulation 8,9 and exerts profound antinociceptive effects in rat and mouse models of acute and chronic pain. 3,9−11 Moreover, it suppresses pain behaviors induced, in mice, by tissue injury, nerve damage, or inflammation.…”

Section: ■ Introductionmentioning

confidence: 99%

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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

et al. 2013

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N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid agonists of peroxisome proliferator-activated receptor-α, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The β-lactone derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)-biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated inflammatory cells, and reduce tissue reactions to pro-inflammatory stimuli. Recently, our group disclosed ARN077 (4), a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia. In the present study, we investigated the structure−activity relationship (SAR) of threonine-derived β-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of β-lactone carbamate derivatives for NAAA and the identification of (4-phenylphenyl)-methyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate (14q) as the first single-digit nanomolar inhibitor of intracellular NAAA activity (IC 50 = 7 nM on both rat NAAA and human NAAA).

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Section: ■ Chemistrymentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2013

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“…1−3 An endogenous FAE that has attracted considerable attention is palmitoylethanolamide (PEA), 4,5 which has been found to modulate pain and inflammation by engaging peroxisome proliferator-activated receptor type α. 6,7 In particular, PEA has been shown to inhibit peripheral inflammation and mast cell degranulation 8 and to exert antinociceptive effects in rodent models of acute and chronic pain. 9 PEA has also been found to suppress pain behaviors induced by tissue injury, nerve damage, or inflammation in mice.…”

Section: ■ Introductionmentioning

confidence: 99%

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

et al. 2012

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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure−activity and structure−property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC 50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.

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“…6,7 In particular, palmitoylethanolamide (PEA), the endogenous amide of palmitic acid and ethanolamine, has been shown to inhibit peripheral inflammation and mast cell degranulation 8,9 and to exhibit antinociceptive properties in rat and mouse models of acute and chronic pain. 10−12 Furthermore, PEA has been indicated to attenuate skin inflammation 13,14 and neuropathic pain in humans.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation, and 3D QSAR Study of 2-Methyl-4-oxo-3-oxetanylcarbamic Acid Esters as N-Acylethanolamine Acid Amidase (NAAA) Inhibitors

et al. 2014

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N-(2-Oxo-3-oxetanyl)carbamic acid esters have recently been reported to be noncompetitive inhibitors of the Nacylethanolamine acid amidase (NAAA) potentially useful for the treatment of pain and inflammation. In the present study, we further explored the structure−activity relationships of the carbamic acid ester side chain of 2-methyl-4-oxo-3-oxetanylcarbamic acid ester derivatives. Additional favorable features in the design of potent NAAA inhibitors have been found together with the identification of a single digit nanomolar inhibitor. In addition, we devised a 3D QSAR using the atomic property field method. The model turned out to be able to account for the structural variability and was prospectively validated by designing, synthesizing, and testing novel inhibitors. The fairly good agreement between predictions and experimental potency values points to this 3D QSAR model as the first example of quantitative structure−activity relationships in the field of NAAA inhibitors.

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Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor-α Agonist, Modulates Carrageenan-Induced Paw Edema in Mice

Cited by 133 publications

References 39 publications

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

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

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

Synthesis, Biological Evaluation, and 3D QSAR Study of 2-Methyl-4-oxo-3-oxetanylcarbamic Acid Esters as N-Acylethanolamine Acid Amidase (NAAA) Inhibitors

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