NAAA Inhibitors as Anti-inflammatory Agents, Phase II

NAAA 抑制剂作为抗炎剂，II 期

• 批准号: 9201955
• 负责人: Shakiru Olajire Alapafuja
• 金额: $ 64.62万
• 依托单位: MAKSCIENTIFIC, LLC
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201955
• 关键词: Acids; Acute; Adverse effects; Ames Assay; Amidohydrolases; Animal Model; Anti-Inflammatory Agents; Asses; Autoimmune Process; Biological Assay; Biological Availability; Charge; Chemical Models; Chronic; Clinical; Clinical Trials; Colitis; Collaborations; Colon; Computer Simulation; Crohn' s disease; Cysteine; Data; Development; Disease; Drug Exposure; Drug Kinetics; Enzymes; Evaluation; Fluorescence; Gastroenterology; Generations; Housing; Human; Immunological Models; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Israel; Joints; Lead; Life; Ligands; Link; Lipids; Liver; Malignant Neoplasms; Mammalian Cell; Medical center; Medicine; Metabolic; Methods; Modeling; Mus; Nuclear Receptors; Oral; Pain; Pathology; Patient Selection; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plasma; Play; Preventive; Process; Property; Reaction; Regulation; Research; Risk; Role; Safety; Scientist; Sensitivity and Specificity; Series; Serine Hydrolase; Signal Transduction; Small Business Innovation Research Grant; Staging; TNF gene; Techniques; Therapeutic; Triage; Ulcerative Colitis; Universities; Work; absorption; abstracting; amidase; analog; base; biophysical model; carboxylate; cost; design; drug discovery; drug efficacy; drug testing; effective therapy; expectation; human disease; improved; in vitro activity; inflammatory pain; inhibitor/antagonist; insight; milligram; mouse model; neuroinflammation; new therapeutic target; novel; novel therapeutics; palmidrol; pharmacophore; pre-clinical; precision medicine; prevent; professor; programs; research study; screening; standard care; therapeutic development; tool; water solubility

OTHER PROJECT INFORMATION - ITEM 7 - 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 AM9053 ameliorates all signs of colon inflammation in mice. Notwithstanding its promising pharmacological profile, AM9053 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 2-3 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.

其他项目信息 - 第 7 项 - 项目摘要/摘要： N-酰基乙醇胺水解酰胺酶 (NAAA) 是一种溶酶体酶，在 N-棕榈酰乙醇胺 (PEA) 失活。 PEA 是一种按需合成的内源性脂质 大多数哺乳动物细胞和越来越多的证据表明 PEA 与炎症和疼痛的调节有关 流程。 我们是第一个在溃疡性结肠炎动物模型中展示并验证我们的内部 NAAA 抑制剂 AM9053 可改善小鼠结肠炎症的所有症状。尽管其药理前景广阔 概况，AM9053 缺乏推进候选药物开发所需的药理学概况 由于肝微粒体稳定性差和口服生物利用度有限，因此需要发现进展 并开发具有合适成药特性的新优化类似物。在第一阶段计划期间， 我们与该中心合作，确定了两个新系列的有效和选择性 NAAA 抑制剂 东北大学药物发现（CDD）。在此应用中，我们建议充分优化配体 效力、选择性和化合物成药性特性，期望确定 2-3 个候选药物 作为治疗溃疡性结肠炎的候选药物取得进展。我们的设计得到了帮助 计算机和生物物理建模技术，旨在优化药物的药效特征 提议的类似物。我们预计这种优化将是一项持续的迭代工作，其中来自早期结果的数据 使用我们的配体设计概念进行了详细阐述。我们还将研究潜在的药理作用 NAAA 抑制剂在肠道局部发挥作用，作为胃肠道炎症的新疗法的优势。 通过限制全身药物，胃肠道限制治疗可能作为治疗 IDB 疾病的更安全药物具有优势 接触。我们工作的意义在于它可能会导致改进药物疗法的发展 这可以减轻与炎症性疾病相关的高昂个人和社会成本。 旨在发现新型可成药 NAAA 抑制剂的药物发现工作是一项联合协作工作 与东北大学药物发现中心 (CDD) 合作。 CDD科学家已克隆、表达 纯化了毫克量的 NAAA，并开发了基于荧光的药物筛选测定法 评估。我们还与贝斯以色列女执事医疗中心的 Kokkotou 教授合作。的 胃肠病学（BIDMC，哈佛大学）在溃疡性结肠炎临床前动物模型中评估我们的化合物 结肠炎。 Kokkotou 教授还将在离体研究中用粘膜外植体评估我们的 NAAA 抑制剂 IBD 患者寻求 NAAA 抑制 IBD 炎症条件的早期原理验证 患者。