A Multi-Disciplinary Approach for the Discovery of Novel Inhibitors of N-Acylethanolamine Acid Amidase

Research Category: Health Sciences
Presenter: Matthew Neale
PI: Spiro Pavlopoulos

N-acylethanolamine hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that hydrolyzes palmitoylethanolamine (PEA), an endogenous ligand long known to attenuate inflammation in disease states such as rheumatoid arthritis and osteoarthritis.  In addition PEA has also shown utility in analgesia, anti-epilepsy, and neuroprotection.  The prolonged direct use of PEA, however, is associated with multiple adverse effects including oncogenesis, renal dysfunction and cardiovascular toxicity.  For this reason, NAAA has been sought as a possible drug target. Inhibitors of NAAA would prevent endogenous PEA metabolism and prolong an anti-inflammatory response. This general strategy of exerting therapeutic biological effects by boosting levels of endogenous ligands through inhibition of metabolizing enzymes holds great promise for highly efficacious medications with greatly reduced side effects.

At present, the few inhibitors of NAAA that are known are metabolically unstable and little is known about the structure of the enzyme. We present a multi-disciplinary approach towards the exploitation of NAAA as a drug target.  This involves a medicinal chemistry effort to design potent, selective inhibitors.  We developed a fluorescent inhibitor assay to quickly evaluate structure activity relationships.  This is coupled with biochemical and biophysical (NMR, MS, Molecular-modeling) characterization of the NAAA active site in order to guide medicinal chemistry efforts. Our novel compound AM9053 (IC50 = 39nM) was recently shown to be very efficacious in the treatment of an irritable bowel syndrome test in rats.  Currently, we are engaged in a lead optimization effort aimed at obtaining early stage NAAA inhibitors with favorable druggability profiles.

NIDA grants (DA3801, DA037575).