NAAA Inhibitors for pain and inflammation

NAAA 疼痛和炎症抑制剂

• 批准号: 8903152
• 负责人: Roger Heim
• 金额: $ 22.39万
• 依托单位: ANTEANA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903152
• 关键词: 3-Dimensional; Absence of pain sensation; Accounting; Acids; Address; Adverse effects; Amidohydrolases; Analgesics; Animals; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Bile Acids; Biochemical; Biological Assay; Cataloging; Catalogs; Cells; Cellular Assay; Ceramidase; Chemicals; Chronic Disease; Chronic inflammatory pain; Clinical; Collaborations; Collection; Computer Simulation; Computing Methodologies; Cysteine; Data; Development; Direct Costs; Disease; Dose; Drug Kinetics; Enzymes; Facilities and Administrative Costs; Fatty Acids; Generations; Homology Modeling; Human; Hydrolase; Hyperalgesia; In Vitro; Inflammation; Inflammatory; Lead; Libraries; Lipids; Medical; Metabolic; Metabolism; Methods; Microsomes; Modeling; Molecular; Narcotics; Neurons; Nociception; Opiates; Pain; Pain management; Patients; Persistent pain; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Play; Powder dose form; Process; Property; Rattus; Research; Risk; Rodent Model; Running; Safety; Sampling; Signal Transduction; Site; Small Business Innovation Research Grant; Specificity; Testing; addiction; allodynia; amidase; analog; analytical method; base; chronic pain; design; effective therapy; high throughput screening; improved; in vitro Assay; inhibitor/antagonist; lead series; lipid mediator; novel; novel strategies; palmidrol; programs; public health relevance; receptor; response; scaffold; screening; small molecule; small molecule libraries; virtual

 DESCRIPTION (provided by applicant): 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.

 描述(由申请人提供)：慢性疼痛治疗在直接和间接成本中约占1000亿美元。目前的治疗方法未能有效地解决这一巨大的医疗问题：麻醉药品导致成瘾和安全风险，而其他类型的止痛药则因疗效不足和副作用而受到阻碍。慢性疼痛是一种进行性疾病，由于慢性疾病(如炎症)的存在，常会出现持续性的痛觉异常和痛觉过敏。因此，迫切需要开发新的、安全的治疗方法，以纠正慢性炎症性疼痛的病理机制。我们建议与皮奥梅利博士(加州大学欧文分校)合作开发新的N-乙醇胺水解酸酰胺酶(NAAA)抑制剂。皮奥梅利博士是包括NAAA信号在内的内源性脂质介质领域公认的世界领先者。NAAA是一种酶，它是一个关键的炎症检查点，通过降解棕榈酰乙醇胺(PEA)来调节疼痛过程，PEA是一种在广泛的啮齿动物模型中发挥深刻止痛和抗炎作用的脂质。此外，PEA在临床疼痛中具有止痛作用，已被用于有效治疗患者的疼痛状况，但PEA代谢不稳定，药代动力学(PK)较差。一种更好的方法可能是抑制NAAA升高炎症和伤害性部位的PEA水平，从而产生抗炎和镇痛反应，但到目前为止，仅有少数全身性PK较差的NAAA抑制剂被描述。由于缺乏与高通量筛选(HTS)兼容的分析方法，阻碍了适合于药物优化的新支架的发现。为了克服这一挑战，我们采取了两种方法：(I)我们开发了一种与HTS兼容的新的NAAA分析方法，(Ii)我们建立了一个NAAA的3D同源模型，可以用于执行虚拟屏幕和指导新型抑制剂的设计。使用这一测试，我们对13K不同的化合物进行了中试筛选，并确定了27种新的抑制剂，它们可以阻断NAAA，但不能抑制类似的水解酶。使用3D同源模型，我们已经证明了这些抑制剂在催化口袋中表现出适当的相互作用。此外，我们对200万种商业化合物进行了虚拟筛选，并检测到更多具有抑制活性的点击。本提案的前两个目标将集中于(目标1) 完成我们的58K小分子文库的HTS和(目标2)所有虚拟筛选命中的表征。目的#3将确认NAAA的活性，抑制机制，对其他类似水解酶的选择性，以及在细胞检测中的活性。最后一个目标(目标4)将测试其他受体和HERG的脱靶活性，以及体外代谢稳定性。首字母 优先支架的合成孔径雷达将在计算方法的辅助下进行探索。我们将根据药理、化学和代谢特性，优先选择最好的支架进行铅优化。SBIR第二阶段将专注于铅的优化，以提高铅系列的药理和PK。