2. Academic Validation
  3. Discovery and SAR Evolution of Pyrazole Azabicyclo[3.2.1]octane Sulfonamides as a Novel Class of Non-Covalent N-Acylethanolamine-Hydrolyzing Acid Amidase (NAAA) Inhibitors for Oral Administration

Discovery and SAR Evolution of Pyrazole Azabicyclo[3.2.1]octane Sulfonamides as a Novel Class of Non-Covalent N-Acylethanolamine-Hydrolyzing Acid Amidase (NAAA) Inhibitors for Oral Administration

  • J Med Chem. 2021 Sep 23;64(18):13327-13355. doi: 10.1021/acs.jmedchem.1c00575.
Paolo Di Fruscia 1,  Anna Carbone 1 2,  Giovanni Bottegoni 3,  Francesco Berti 1,  Francesca Giacomina 1,  Stefano Ponzano 1,  Chiara Pagliuca 1,  Annalisa Fiasella 1,  Daniela Pizzirani 1,  Jose Antonio Ortega 1,  Andrea Nuzzi 1,  Glauco Tarozzo 1,  Luisa Mengatto 1,  Roberta Giampà 1,  Ilaria Penna 1,  Debora Russo 1,  Elisa Romeo 4,  Maria Summa 5,  Rosalia Bertorelli 5,  Andrea Armirotti 5,  Sine Mandrup Bertozzi 5,  Angelo Reggiani 4,  Tiziano Bandiera 1,  Fabio Bertozzi 1
Affiliations

Affiliations

  • 1 D3-PharmaChemistry, Istituto Italiano di Tecnologia (IIT), 16163Genova, Italy.
  • 2 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90123Palermo, Italy.
  • 3 Computational and Chemical Biology, Istituto Italiano di Tecnologia (IIT), 16163Genova, Italy.
  • 4 D3-Validation, Istituto Italiano di Tecnologia (IIT), 16163Genova, Italy.
  • 5 Analytical Chemistry and Translational Pharmacology, Istituto Italiano di Tecnologia (IIT), 16163Genova, Italy.
PMID: 34469137 DOI: 10.1021/acs.jmedchem.1c00575
Abstract

Inhibition of intracellular N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclo[3.2.1]octane structural core. After an initial screening campaign, a careful structure-activity relationship study led to the discovery of endo-ethoxymethyl-pyrazinyloxy-8-azabicyclo[3.2.1]octane-pyrazole sulfonamide 50 (ARN19689), which was found to inhibit human NAAA in the low nanomolar range (IC50 = 0.042 μM) with a non-covalent mechanism of action. In light of its favorable biochemical, in vitro and in vivo drug-like profile, sulfonamide 50 could be regarded as a promising pharmacological tool to be further investigated in the field of inflammatory conditions.

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