Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis
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- 作者：Dr. Marco Migliore ; Dr. Silvia Pontis ; Dr. Angel Luis Fuentes de Arriba ; Dr. Natalia Realini ; Dr. Esther Torrente ; Dr. Andrea Armirotti ; Dr. Elisa Romeo ; Dr. Simona Di Martino ; Dr. Debora Russo ; Dr. Daniela Pizzirani ; Dr. Maria Summa ; Dr. Massimiliano Lanfranco ; Dr. Giuliana Ottonello ; Dr. Perrine Busquet ; Dr. Kwang-Mook Jung ; Dr. Miguel Garcia-Guzman ; Dr. Roger Heim ; Dr. Rita Scarpelli and Prof. Daniele Piomelli
- 刊名：Angewandte Chemie
- 出版年：2016
- 出版时间：September 5, 2016
- 年：2016
- 卷：128
- 期：37
- 页码：11359-11363
- 全文大小：1110K
- ISSN：1521-3757
文摘
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.