Second‐Generation Non‐Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis. Issue 37 (12th July 2016)

• Record Type: Journal Article
• Authors: Migliore, Marco; Pontis, Silvia; Fuentes de Arriba, Angel Luis; Realini, Natalia; Torrente, Esther; Armirotti, Andrea; Romeo, Elisa; Di Martino, Simona; Russo, Debora; Pizzirani, Daniela; Summa, Maria; Lanfranco, Massimiliano; Ottonello, Giuliana; Busquet, Perrine; Jung, Kwang‐Mook; Garcia‐Guzman, Miguel; Heim, Roger; Scarpelli, Rita; Piomelli, Daniele
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 37(2016)
• Page Start: 11193
• Page End: 11197
• Publication Date: 2016-07-12
• Subjects: cysteine hydrolase -- fatty acylethanolamides -- multiple sclerosis -- N-acylethanolamine acid amidase -- neuroinflammation; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201603746
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : Treating neuroinflammation : The cysteine amidase N ‐acyl ethanolamine acid amidase (NAAA) promotes inflammation by degrading endogenous anti‐ inflammatory lipid amides such as palmitoylethanolamide (PEA). A new class of non‐covalent, orally available NAAA inhibitors (see example) interrupt NAAA‐mediated lipid amide degradation in the brain, and are strongly protective in a mouse model of neuroinflammation.