NAAA Inhibitors as Anti inflammatory Agents Phase II

OTHER PROJECT INFORMATION ITEM PROJECT SUMMARY ABSTRACT 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 We are the first to show and validate in animal models of ulcerative colitis that our in house NAAA inhibitor AM ameliorates all signs of colon inflammation in mice Notwithstanding its promising pharmacological profile AM lacked the desired pharmacological profile for advancing to candidate developed advancement due to poor liver microsomal stability and limited oral bioavailability thus requiring the discovery and development of new optimized analogs with suitable druggability properties During the Phase I program we have identified two new series of potent and selective NAAA inhibitors in collaboration with the Center for Drug Discovery CDD at Northeastern University In this application we propose to fully optimize ligand potency selectivity and compound druggability properties with the expectation to identify candidates for advancement as development candidates for the treatment of ulcerative colitis Our design is aided by computer and biophysical modeling techniques 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 effort aimed at discovering novel druggable NAAA inhibitors is a joint 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 also collaborate with Professor Kokkotou at Beth Israel Deaconess Medical Center Div of Gastroenterology BIDMC Harvard to evaluate our compounds in preclinical animal models of ulcerative colitis Professor Kokkotou will also asses our NAAA inhibitors in ex vivo studies with mucosal explants from patients with IBD seeking an early proof of principle of NAAA inhibition in inflammatory conditions in IBD patients OTHER PROJECT INFORMATION ITEM PROJECT NARRATIVE NAAA Inhibitors as Anti Inflammatory Agents N Acylethanolamine hydrolyzing acid amidase NAAA is a novel drug target that offers a safer alternate approach to the treatment of GI inflammatory diseases without the severe side effects of current medications Pharmacologic strategies aimed at correcting a deficit in PEA PPARa signaling by preventing PEA degradation with highly specific and efficacious inhibitors of NAAA may yield insights to the role PPAR in chronic GI inflammatory conditions and other pathologies such as neuroinflammation and pain