N-Acylethanolamine acid amidase (NAAA), an N-terminal cysteine hydrolase, primarily exists in the endosomal-lysosomal compartment of innate and adaptive immune cells. NAAA, a member of the choloylglycine hydrolase family, is a subclass of the N-terminal nucleophile hydrolase (Ntn) superfamily. Importantly, NAAA is together with fatty acid amide hydrolase (FAAH), contributes to the deactivating cleavage of palmitoylethanolamide (PEA) to palmitic acid and ethanolamine. NAAA exhibits optimal activity at acidic pH. PEA is a lipid-derived PPAR-α agonist that exhibits analgesic, anti-inflammation, and anti-multiple sclerosis activities. Therefore, the development of NAAA inhibitors may represent a novel frontier for the treatment of inflammatory disorders.
According to reports, several series of compounds targeting NAAA inhibition have potential therapeutic use for inflammatory and neuropathic pain, multiple sclerosis, allergic dermatitis, arthritis, and inflammatory bowel diseases. However, the number of reported NAAA inhibitors remains limited and is mainly due to the restricted substrate-binding site of NAAA. The catalytic cavity of NAAA is suitable for accommodating only narrow and relatively straight compound backbones. Furthermore, identifying specific molecular structures to fit the catalytic center of this enzyme remains a challenge for synthetic chemists.
ARN19689 is a selective, orally active and non-covalent inhibitor of NAAA.
ARN19689, an azabicyclic compound, is a potent and orally active inhibitor of NAAA. In biological assays, ARN19689 shows a very high selectivity toward both human FAAH and human acid ceramidase. ARN19689 has no reactive chemical moieties toward the catalytic cysteine, and interacts with h-NAAA non-covalently. ARN19689 prevents the binding of the activity-based probe (ABP) ARN14686 to h-NAAA in cell lysosomal extracts in a 15 min incubation experiment. Besides, ARN19689 exhibits high plasma concentrations following i.v. and p.o. administration, low volume of distribution and clearance, and good oral bioavailability. Therefore, ARN19689 is a promising pharmacological tool to be further investigated in the field of inflammatory conditions.
All in all, ARN19689 is a potent, selective, orally active and non-covalent inhibitor of NAAA.