NAAA Inhibitors as Anti-inflammatory Agents, Phase II

其他项目信息-项目7 -项目概要/摘要： N-酰基乙醇胺水解酸性酰胺酶（NAAA）是一种溶酶体酶，其在细胞内的蛋白质合成中起核心作用。 N-棕榈酰乙醇胺（PEA）的失活。PEA是一种内源性脂质，通过按需合成产生， 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证明和验证我们的内部NAAA抑制剂 AM 9053改善小鼠中结肠炎症的所有体征。尽管其有前途的药理学 由于AM 9053的药理学特征，AM 9053缺乏推进候选药物开发所需的药理学特征 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 以及开发具有合适的可药用特性的新的优化类似物。在第一阶段计划中， 我们已经确定了两个新的系列有效的和选择性的NAAA抑制剂与中心合作， 东北大学的药物发现（CDD）。在这个应用中，我们建议充分优化配体 效力、选择性和化合物可药用性性质，期望鉴定2-3种候选物， 作为溃疡性结肠炎治疗的开发候选者的进展。我们的设计得到了 计算机和生物物理建模技术，旨在优化的药效学特征， 提出的类比。我们希望这种优化是一个持续的迭代工作，其中来自早期结果的数据 都是用我们的配体设计概念来阐述的。我们还将研究潜在的药理作用 和NAAA抑制剂作为GI炎症性疾病的新型疗法在肠道局部作用的优点。 GI限制治疗可通过限制全身用药，作为更安全的IDB疾病药物提供优势 exposure.我们的工作的意义在于它可能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的个人和社会成本。 旨在发现新型可药用NAAA抑制剂的药物发现工作是一项联合合作努力 东北大学药物发现中心（CDD）。CDD的科学家们克隆了 和纯化毫克量的NAAA，并开发了基于荧光的药物筛选试验， 考核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），以评估我们的化合物在溃疡性结肠炎临床前动物模型中的作用。 结肠炎Kokkotou教授还将评估我们的NAAA抑制剂在离体研究中的粘膜外植体， IBD患者寻求IBD炎症性疾病中NAAA抑制的早期原理验证 患者

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.