arn-077

Description: ARN 077 (ARN-077) is a novel, potent and selective N-acylethanolamine acid amidase (NAAA) inhibitor with an IC50 of 7 nM for human NAAA. ARN 077 significantly increases palmitoyl ethanolamine (PEA) levels within the CNS and has broad antinociceptive activity in mice and rats. Topical administration of ARN077 attenuated, in a dose-dependent manner, heat hyperalgesia and mechanical allodynia elicited in mice by carrageenan injection or sciatic nerve ligation. The antinociceptive effects of ARN077 were prevented by the selective PPAR-alpha antagonist GW6471 and did not occur in PPAR-alpha-deficient mice. Furthermore, topical ARN077 reversed the allodynia caused by ultraviolet B radiation in rats, and this effect was blocked by pretreatment with GW6471. Sciatic nerve ligation or application of the proinflammatory phorbol ester 12-O-tetradecanoylphorbol 13-acetate decreased FAE levels in sciatic nerve and skin tissue, respectively. ARN077 reversed these biochemical effects. The results identify ARN077 as a potent inhibitor of intracellular NAAA activity, which is active in vivo by topical administration. The findings further suggest that NAAA regulates peripheral pain initiation by interrupting endogenous FAE signaling at PPAR-alpha.

References: Pain. 2013 Mar; 154(3):350-60.