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

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RESEARCH PRODUCT

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

Andrea Armirotti Debora Russo Andrea Nuzzi Paolo Di Fruscia Daniela Pizzirani Chiara Pagliuca Giovanni Bottegoni Annalisa Fiasella Ilaria Penna Jose Antonio Ortega Elisa Romeo Francesca Giacomina Sine Mandrup Bertozzi Angelo Reggiani Maria Summa Anna Carbone Anna Carbone Roberta Giampà Rosalia Bertorelli Francesco Berti Tiziano Bandiera Luisa Mengatto Stefano Ponzano Glauco Tarozzo Fabio Bertozzi

subject

Male Stereochemistry Anti-Inflammatory Agents Peptides and proteins Pyrazole Article Amidohydrolases Amidase Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound In vivo N-Acylethanolamine Drug Discovery medicine Animals Humans Sulfones Enzyme Inhibitors IC50 Inhibition Inflammation chemistry.chemical_classification Palmitoylethanolamide Molecular Structure Inhibitors Sulfonamide Mice Inbred C57BL Molecular Docking Simulation Mechanism of action chemistry Microsomes Liver Inhibitors Inhibition Sulfones Peptides and proteins Inflammation Pyrazoles Molecular Medicine medicine.symptom Protein Binding Tropanes

description

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.

year	journal	country	edition	language
2021-09-01	Journal of Medicinal Chemistry

https://doi.org/10.1021/acs.jmedchem.1c00575