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