title: Synthesis and structure-activity relationships of N-(2-oxo-3-oxetanyl)amides as N-acylethanolamine-hydrolyzing acid amidase inhibitors.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of California, Irvine, 360 MSRII, Irvine, California 92697-4625, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.forename: Francesca
authors.initials: F
authors.lastname: Antonietti
authors.forename: Andrea
authors.initials: A
authors.lastname: Duranti
authors.forename: Andrea
authors.initials: A
authors.lastname: Tontini
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: 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
chemical_list: 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