title: Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies.
abstract: 4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b. This favourable profile, along with the structural diversity of the carbamic acid chain of 3b, identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: andrea.nuzzi@ndm.ox.ac.uk.
authors: Andrea
authors: A
authors: Nuzzi
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: afiasella@gmail.com.
authors: Annalisa
authors: A
authors: Fiasella
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Jose Antonio
authors: JA
authors: Ortega
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Chiara
authors: C
authors: Pagliuca
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Stefano
authors: S
authors: Ponzano
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Daniela
authors: D
authors: Pizzirani
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Sine Mandrup
authors: SM
authors: Bertozzi
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Giuliana
authors: G
authors: Ottonello
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: glauco.tarozzo@evotec.com.
authors: Glauco
authors: G
authors: Tarozzo
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Angelo
authors: A
authors: Reggiani
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Tiziano
authors: T
authors: Bandiera
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: fabio.bertozzi@iit.it.
authors: Fabio
authors: F
authors: Bertozzi
authors: Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy; Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine 92697-4625, USA. Electronic address: daniele.piomelli@iit.it.
authors: Daniele
authors: D
authors: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000611961:(2,2-difluoro-1,3-benzodioxol-5-yl)-methyl-N-(2-oxoazetidin-3-yl)carbamate; D002219:Carbamates; D004791:Enzyme Inhibitors; D004952:Esters; D047090:beta-Lactams; D000581:Amidohydrolases; C523108:NAAA protein, human
keywords: Carbamates; Cysteine hydrolase; Inhibitors; N-acylethanolamine acid amidase; Structure–activity relationships; β-lactams