Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis
Dr. Marco Migliore
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
These authors contributed equally to this work.
Search for more papers by this authorDr. Silvia Pontis
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
These authors contributed equally to this work.
Search for more papers by this authorDr. Angel Luis Fuentes de Arriba
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Natalia Realini
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Esther Torrente
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Andrea Armirotti
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Elisa Romeo
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Simona Di Martino
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Debora Russo
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Daniela Pizzirani
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Maria Summa
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Massimiliano Lanfranco
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Giuliana Ottonello
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Perrine Busquet
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Kwang-Mook Jung
Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA, 92697-4625 USA
Search for more papers by this authorDr. Miguel Garcia-Guzman
Anteana Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego, CA, 92121 USA
Search for more papers by this authorDr. Roger Heim
Anteana Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego, CA, 92121 USA
Search for more papers by this authorCorresponding Author
Dr. Rita Scarpelli
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorCorresponding Author
Prof. Daniele Piomelli
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA, 92697-4625 USA
Search for more papers by this authorDr. Marco Migliore
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
These authors contributed equally to this work.
Search for more papers by this authorDr. Silvia Pontis
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
These authors contributed equally to this work.
Search for more papers by this authorDr. Angel Luis Fuentes de Arriba
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Natalia Realini
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Esther Torrente
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Andrea Armirotti
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Elisa Romeo
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Simona Di Martino
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Debora Russo
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Daniela Pizzirani
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Maria Summa
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Massimiliano Lanfranco
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Giuliana Ottonello
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Perrine Busquet
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorDr. Kwang-Mook Jung
Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA, 92697-4625 USA
Search for more papers by this authorDr. Miguel Garcia-Guzman
Anteana Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego, CA, 92121 USA
Search for more papers by this authorDr. Roger Heim
Anteana Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego, CA, 92121 USA
Search for more papers by this authorCorresponding Author
Dr. Rita Scarpelli
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Search for more papers by this authorCorresponding Author
Prof. Daniele Piomelli
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy
Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA, 92697-4625 USA
Search for more papers by this authorAbstract
Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole–piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders.
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