N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme, which plays a central role in the deactivation of N-palmitoylethanolamine (PEA). PEA is an endogenous lipid produced on-demand synthesis by most mammalian cells and a growing body of evidence links PEA in the regulation of inflammatory and pain processes. In this application, we propose to develop potent and selective NAAA inhibitors with drug-like properties to serve as a basis for evaluation in preclinical animal models of inflammatory diseases. Early pharmacological probes of NAAA inhibition showed modest potencies or have poor drug-like properties limiting their potential as drugs. Thus, new generations of druggable NAAA inhibitors are in great need as potential safer therapies for treating inflammatory conditions. We have identified new series of potent NAAA inhibitors in collaboration with the Center for Drug Discovery (CDD) at Northeastern University. The new generation inhibitors showed good potency for NAAA and have demonstrated better physicochemical properties than earlier inhibitors. Our design is aided by computer modeling approaches aimed at optimizing the pharmacophoric features of the proposed analogs. We expect this optimization to be an ongoing iterative effort in which data from early results are elaborated using our ligand design concepts. We will also investigate the potential pharmacological role and advantages of NAAA inhibitors acting locally at the gut as novel therapies for GI inflammatory conditions. GI restricted treatments may offer advantages as safer medicines for IDB illnesses by limiting systemic drug exposure. The significance of our work is that it may lead to the development of improved pharmacotherapies that could ease the high personal and societal costs associated with inflammatory diseases. The drug discovery investigation of NAAA inhibition is a joined collaborative effort with the Center for Drug Discovery (CDD) at Northeastern University. CDD scientists have cloned, expressed and purified milligram amounts of NAAA, and developed fluorescence-based screening assays for drug assessment. We expect to obtain 2-3 successful compounds. These will serve as leads for our Phase II project during which we shall engage in a lead optimization effort. In vivo characterization of the later generation inhibitors will be evaluated in vivo in collaboration with Dr. D. Piomelli's laboratory.