NAAA Inhibitors for pain and inflammation

DESCRIPTION provided by applicant Chronic pain management accounts for approximately US$ billion in direct and indirect costs Current treatments fail to address effectively this large medical problem narcotics cause addiction and safety risks while other types of analgesics are hampered by insufficient efficacy and side effects Chronic pain is a progressive condition where persistent allodynia and hyperalgesia often emerge due to the presence of chronic disease e g inflammation Therefore there is a critical need to develop novel safe therapies that can rectify pathological mechanisms involved in chronic inflammatory pain We propose to develop novel inhibitors of N acylethanolamine hydrolyzing acid amidase NAAA in collaboration with Dr Piomelli UC Irvine who is a recognized world leader in the field of endogenous lipid mediators including NAAA signaling NAAA is an enzyme that serves as a key inflammatory checkpoint and regulates pain processing by degrading palmitoylethanolamine PEA a lipid that exerts profound analgesic and anti inflammatory effects in a broad range of rodent models Moreover PEA is analgesic in clinical pain and has been used to treat effectively pain conditions in patients but PEA is metabolically labile and has poor pharmacokinetics PK A better approach may be to inhibit NAAA to elevate PEA levels at inflammatory and nociceptive sites resulting in anti inflammatory and analgesic responses but so far only a few NAAA inhibitors with poor systemic PK have been described The discovery of new scaffolds suitable for drug optimization has been hindered by the lack of assays compatible with high throughput screening HTS To overcome this challenge we are taking two approaches i we developed a new NAAA assay that is compatible with HTS and ii we built a D homology model of NAAA that can be used to execute virtual screens and guide the design of novel inhibitors Using this assay we ran a pilot screen of K diverse compounds and identified novel inhibitors that block NAAA but do not inhibit similar hydrolases Using the D homology model we have shown that these inhibitors display proper interactions in the catalytic pocket In addition we ran a virtual screening of million commercial compounds and detected additional hits with inhibitory activity The first two aims of this proposal will focus on Aim completing the HTS of our library of K small molecules and Aim the characterization of all the virtual screening hits Aim will confirm activity on NAAA mechanisms of inhibition selectivity over other similar hydrolases and activity in cellular assays The last aim Aim wil test for off target activity on other receptors and hERG and metabolic stability in vitro Initial SAR of prioritized scaffolds will be explored assisted by computational methods We will prioritize the best scaffolds for lead optimization based on pharmacology chemical and metabolic properties The SBIR phase II will focus on lead optimization to improve the pharmacology and PK of lead series PUBLIC HEALTH RELEVANCE There is a critical need to develop novel treatments for chronic inflammatory pain Optimal treatments will have to achieve good safety and effective analgesia while reversing inflammation and neuronal alterations responsible of generating persistent pain We propose to develop novel inhibitors of a new enzyme that plays a key role in inflammation and pain Extensive research with animals and patients with chronic pain support the rationale of our approach We are using a new high throughput molecular screening and computational modeling to identify novel chemical compounds that can be optimized as drugs Drug products developed in this program could reverse inflammation and have a disease modifying action in chronic pain conditions