title: Progress in the development of β-lactams as N-Acylethanolamine Acid Amidase (NAAA) inhibitors: Synthesis and SAR study of new, potent N-O-substituted derivatives.
abstract: The anti-inflammatory effects resulting from raising the levels of palmitoylethanolamide (PEA), an endogenous bioactive lipid, led to envisage N-Acylethanolamine Acid Amidase (NAAA), the cysteine hydrolase mainly responsible for PEA degradation, as an attractive target for small molecule inhibitors. Previous work in our group identified serine-derived β-lactams as potent and systemically active inhibitors of NAAA activity. Aiming to expand the SAR study around this class of compounds, we investigated the effect of the substitution on the endocyclic nitrogen by designing and synthesizing a series of N-substituted β-lactams. The present work describes the synthesis of new N-O-alkyl and N-O-aryl substituted β-lactams and reports the results of the structure activity relationship (SAR) study leading to the discovery of a novel, single-digit nanomolar NAAA inhibitor (37). Compound 37 was shown in vitro to inhibit human NAAA via S-acylation of the catalytic cysteine, and to display very good selectivity vs. human Acid Ceramidase, a cysteine amidase structurally related to NAAA. Preliminary in vivo studies showed that compound 37, administered topically, reduced paw edema and heat hyperalgesia in a carrageenan-induced inflammation mouse model. The high in vitro potency of 37 as NAAA inhibitor, and its encouraging in vivo activity qualify this compound as a new tool for the study of the role of NAAA in inflammatory and pain states.
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Petracca
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ponzano
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy.
authors.forename: S M
authors.initials: SM
authors.lastname: Bertozzi
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Sasso
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy; Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, 92697-4625 Irvine, USA.
authors.forename: D
authors.initials: D
authors.lastname: Piomelli
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Bandiera
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy. Electronic address: fabio.bertozzi@iit.it.
authors.forename: F
authors.initials: F
authors.lastname: Bertozzi
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D010146:Pain / Q000188:drug therapy; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D047090:beta-Lactams; D000581:Amidohydrolases; C523108:NAAA protein, human
keywords: Cysteine hydrolase; Inhibitors; N-Acylethanolamine acid amidase; N-O-Substituted β-lactams; Structure–activity relationships (SAR)