Ethanoloamides of long-chain fatty acids, termed N-acylethanolamines (NAEs) have been reported to have a variety of biological activities. NAEs are a substrate of N-acylethanolamine-hydrolyzing acid amidase (NAAA) that catalytically hydrolyze NAEs to ethanolamine and the corresponding fatty acid. The catalytic activity of NAAA is distinct from that of fatty acid amide hydrolase (FAAH) and NAAA exhibits a preference for N-palmitoylethanolamine (PEA) over other NAEs. PEA has anti-inflammatory, anti-nociceptive, immunosuppressive, neuroprotective and also anti-oxidant activity. These characteristics make NAAA an excellent therapeutic target for discovery of novel compounds to treat pain, inflammation, and other conditions that may benefit from modulating the levels of endogenous fatty-acid ethanolamides, particularly PEA.
Current analgesic and anti-inflammatory agents produce side effects, limited efficacy and there remains an unmet need for new therapeutics for pain and inflammatory disorders. UC Irvine investigators have discovered a new class of compounds that inhibit N-acylethanolamine-hydrolyzing acid amidase (NAAA). Several novel NAAA inhibitors showed submicromolar activity in vitro enzymatic assays. Potent and selective compounds were further evaluated for anti-inflammatory effects in animal models. An increase in PEA levels, modulation of the immune cell infiltrate, and a reduction in inflammation were demonstrated. NAAA inhibitors will be useful to alleviate conditions associated with a reduced concentration of N-palmitoylethanolamine (PEA), such as pain and inflammation, and neurodegenerative disorders.
Various NAAA inhibitors were identified that will be useful in the treatment of conditions associated with reduced levels of endogenous ethanolamides. NAAA inhibitors represent therapeutic agents for the treatment of inflammatory diseases (rheumatoid arthritis, osteoarthritis, asthma, psoriasis), pain, metabolic diseases, and neurodegenerative diseases such as Alzheimer's Disease.
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Additional Patent Pending