SBIR-STTR Award

Chronic pain management accounts for approximately US$100 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 3D-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 13K diverse compounds and identified 27 novel inhibitors that block NAAA but do not inhibit similar hydrolases. Using the 3D-homology model we have shown that these inhibitors display proper interactions in the catalytic pocket. In addition, we ran a virtual screening of 2 million commercial compounds and detected additional hits with inhibitory activity. The first two aims of this proposal will focus on (Aim#1) completing the HTS of our library of 58K small molecules and (Aim#2) the characterization of all the virtual screening hits. Aim #3 will confirm activity on NAAA, mechanisms of inhibition, selectivity over other similar hydrolases, and activity in cellular assays. The last aim (Aim#4) 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 Statement:


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.

Project Terms:
3-Dimensional; Absence of pain sensation; Accounting; Acids; addiction; Address; Adverse effects; allodynia; amidase; Amidohydrolases; Analgesics; analog; analytical method; Animals; Anti Inflammatory Analgesics; Anti-inflammatory; Anti-Inflammatory Agents; base; Bile Acids; Biochemical; Biological Assay; Cataloging; Catalogs; Cells; Cellular Assay; Ceramidase; Chemicals; Chronic Disease; Chronic inflammatory pain; chronic pain; Clinical; Collaborations; Collection; Computer Simulation; Computing Methodologies; Cysteine; Data; design; Development; Direct Costs; Disease; Dose; Drug Kinetics; effective therapy; Enzymes; Facilities and Administrative Costs; Fatty Acids; Generations; high throughput screening; Homology Modeling; Human; Hydrolase; Hyperalgesia; improved; In Vitro; in vitro Assay; Inflammation; Inflammatory; inhibitor/antagonist; Lead; lead series; Libraries; lipid mediator; Lipids; Medical; Metabolic; Metabolism; Methods; Microsomes; Modeling; Molecular; Narcotics; Neurons; Nociception; novel; novel strategies; Opiates; Pain; Pain management; palmidrol; Patients; Persistent pain; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Play; Powder dose form; Process; programs; Property; public health relevance; Rattus; receptor; Research; response; Risk; Rodent Model; Running; Safety; Sampling; scaffold; screening; Signal Transduction; Site; Small Business Innovation Research Grant; small molecule; small molecule libraries; Specificity; Testing; virtual

Pain management is a significant unmet medical need. Palmitoylethanolamide (PEA) is an endogenous analgesic substance that plays crucial roles in the peripheral control of pain and inflammation. Its biological actions are terminated by the cysteine hydrolase, N-acylethanolamine acid amidase (NAAA). During the Phase 1 of the present SBIR-2 application, we have developed the first class of potent, selective and orally available NAAA inhibitors. The lead compound in this class, a benzothiazole piperazine derivative called ARN19702, exerts profound analgesic effects in animal models of acute and chronic pain, suggesting that NAAA inhibition may offer a transformative approach to pain therapy. Work done during the Phase 1 of the present application has demonstrated that ARN19702 (i) is a potent and reversible inhibitor of mouse and human NAAA; (ii) displays a high degree of target selectivity when assayed on a panel of 96 receptors, ion channels, enzymes and membrane transporters, or toward other cysteine hydrolases; (iii) is systemically active and, unlike previous NAAA inhibitors, has excellent oral bioavailability; and (iv) suppresses pain with high efficacy and prolonged duration of action in four distinct animal models. Based on these properties, we selected ARN19702 as candidate for preclinical development. The objective of present proposal is to complete all key activities needed to enable the filing of an Investigational New Drug (IND) for ARN19702 in postoperative pain, a market that is now served by addictive opioid drugs or opioid/NSAID combinations. Our specific aims are: Aim 1. Determine the metabolism and pharmacokinetics properties of ARN19702. We will collect the DM-PK data necessary to support the IND filing of ARN19702. Aim 2. Determine the nonclinical toxicology properties of ARN19702. We will collect the toxicology data necessary to support the IND filing of ARN19702. Aim 3. Determine the nonclinical pharmacodynamics of ARN19702. To facilitate the clinical development of ARN19702, we will develop a circulating biomarker for NAAA inhibition and enhancement of PEA-mediated signaling. The studies will be directed by an experienced team of scientists and pharmaceutical professionals, which include NeoKera’s cofounders, Dr. Edward Monaghan (PI) and Professor Daniele Piomelli (co-PI), along with independent consultants Dr. William Schmidt, a clinical pharmacology consultant specialized in pain therapy; Dr. Fred Reno, a consultant in toxicology; Dr. George Mooney, a consultant in Chemistry, Manufacturing and Controls; Dr. Edward (Ned) Whittamore, a consultant in regulatory affairs; Nancy Levine, consultant for pharmacokinetics; and Dr. Joe Rinehart (Vice Chair for Research at UCI’s Department of Anesthesiology) as pro bono clinical consultant. The proposed studies will provide the necessary data in support of an IND filing for ARN19702 as a treatment for general acute pain.

Public Health Relevance Statement:
PROJECT NARRATIVE Opioid painkillers work well in only one quarter of patients and are at the core of an abuse epidemic that has claimed the lives of more than 500,000 Americans from 2000 to 2015. It is clear that we need better ways to control pain. Our lab has discovered a new class of chemicals, called ‘NAAA inhibitors’, which produce powerful pain suppression in animals through a novel non-addictive mechanism: here we propose studies that will enable clinical testing of the first member of this new class of medicines.

Project Terms:
Acids; Acute Pain; Adverse effects; American; amidase; Analgesics; Anesthesiology; Animal Model; Animals; base; benzothiazole; Biological; Biological Assay; Biological Availability; Biology; California; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemistry; chronic pain; circulating biomarkers; Clinical; clinical development; Clinical Pharmacology; Collection; commercialization; Constipation; Cysteine; Data; Development; Drug Combinations; Drug Kinetics; Economics; Enzymes; Epidemic; experience; Goals; Heroin; Human; Hydrolase; Industry; Inflammation; inhibitor/antagonist; Investigation; Investigational Drugs; Investigational New Drug Application; Investments; Ion Channel; Knowledge; Lead; Lipids; Mediating; Medical; Medicine; member; Membrane Transport Proteins; Metabolism; Mus; Non-Steroidal Anti-Inflammatory Agents; novel; novel therapeutics; Opioid; Opioid Analgesics; opioid mortality; opioid therapy; opioid use; Oral; Pain; pain inhibition; Pain management; pain model; pain relief; palmidrol; Patients; Perioperative; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Piperazines; Play; Postoperative Pain; preclinical development; prescription opioid; Privatization; professor; programs; Property; receptor; Regulatory Affairs; Research; research clinical testing; Risk; Role; Safety; Scientist; Signal Transduction; Small Business Innovation Research Grant; Sum; Toxicology; Translating; trend; United States Food and Drug Administration; Universities; Ventilatory Depression; Work