Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies

Andrea Nuzzi; Annalisa Fiasella; Jose Antonio Ortega; Chiara Pagliuca; Stefano Ponzano; Daniela Pizzirani; Sine Mandrup Bertozzi; Giuliana Ottonello; Glauco Tarozzo; Angelo Reggiani; Tiziano Bandiera; Fabio Bertozzi; Daniele Piomelli

doi:10.1016/j.ejmech.2016.01.046

Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies

Eur J Med Chem. 2016 Mar 23:111:138-59. doi: 10.1016/j.ejmech.2016.01.046. Epub 2016 Jan 27.

Affiliations

¹ Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: andrea.nuzzi@ndm.ox.ac.uk.
² Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: afiasella@gmail.com.
³ Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
⁴ Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: glauco.tarozzo@evotec.com.
⁵ Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy. Electronic address: fabio.bertozzi@iit.it.
⁶ 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.

PMID: 26866968
DOI: 10.1016/j.ejmech.2016.01.046

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.

Keywords: Carbamates; Cysteine hydrolase; Inhibitors; N-acylethanolamine acid amidase; Structure–activity relationships; β-lactams.

MeSH terms

Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / metabolism
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Esters / chemical synthesis*
Esters / chemistry
Esters / pharmacology*
Humans
Molecular Structure
Structure-Activity Relationship
beta-Lactams / chemical synthesis
beta-Lactams / chemistry
beta-Lactams / pharmacology*

Substances

(2,2-difluoro-1,3-benzodioxol-5-yl)-methyl-N-(2-oxoazetidin-3-yl)carbamate
Carbamates
Enzyme Inhibitors
Esters
beta-Lactams
Amidohydrolases
NAAA protein, human