Synthesis and structure-activity relationships of N-(2-oxo-3-oxetanyl)amides as N-acylethanolamine-hydrolyzing acid amidase inhibitors.
The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator-activated receptor-alpha, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine-hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a, a series of beta-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC(50) = 420 nM; 7h, IC(50) = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.
Solorzano
Carlos
C
Department of Pharmacology, University of California, Irvine, 360 MSRII, Irvine, California 92697-4625, USA.
Antonietti
Francesca
F
Duranti
Andrea
A
Tontini
Andrea
A
Rivara
Silvia
S
Lodola
Alessio
A
Vacondio
Federica
F
Tarzia
Giorgio
G
Piomelli
Daniele
D
Mor
Marco
M
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002351:Carrageenan; D020134:Catalytic Domain; D002460:Cell Line; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007249:Inflammation / Q000276:immunology; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D004988:Ethers, Cyclic; D007783:Lactones; C551958:N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide; D011994:Recombinant Proteins; D002351:Carrageenan; D000581:Amidohydrolases