Second‐Generation Non‐Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis. (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. Volume 128:Number 37(2016)
• Page Start: 11359
• Page End: 11363
• Publication Date: 2016-07-12
• Subjects: Cystein-Hydrolase -- Fettsäureacylethanolamide -- Multiple Sklerose -- N-Acylethanolaminsäure-Amidase -- Nervenentzündungen; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201603746
• Languages: English
• ISSNs: 0044-8249

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.