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
  • 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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