NAAA Inhibitors as Anti-inflammatory Agents, Phase II

其他项目信息--项目7--项目摘要/摘要： N-乙酰乙醇胺水解酸酰胺酶(NAAA)是一种溶酶体酶，在机体的生长发育过程中起着核心作用。 N-棕榈酰乙醇胺(PEA)的失活。豌豆是一种按需合成的内源性脂质，由 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的动物模型中证明和验证我们的内部NAAA抑制剂 AM9053可改善小鼠结肠炎的所有迹象。尽管它有很好的药理作用 资料，AM9053缺乏所需的药理资料，无法发展为已开发的候选人 由于肝脏微粒体稳定性差和口服生物利用度有限而导致的进展，因此需要发现 以及开发具有合适的可服药特性的新的优化类似物。在第一阶段计划期间， 我们已经确定了两个新的有效和选择性的NAAA抑制剂系列与中心合作 东北大学的药物发现(CDD)。在这一应用中，我们提出了对配体进行充分优化 效力、选择性和复合药效特性，预计确定2-3个候选对象 作为溃疡性结肠炎治疗候选药物的研究进展。我们的设计得到了 计算机和生物物理建模技术，旨在优化药物的药效特征 建议的类比。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 都是使用我们的配体设计概念来阐述的。我们还将研究其潜在的药理作用 以及在肠道局部作用的NAAA抑制剂作为治疗胃肠道炎症条件的新疗法的优势。 通过限制全身用药，GI限制治疗可能会为IDB疾病提供更安全的药物 曝光。我们工作的意义在于，它可能会导致改进药物疗法的发展 这可能会缓解与炎症性疾病相关的高昂的个人和社会成本。 旨在发现新的NAAA抑制剂的药物发现工作是一项共同的合作努力。 与东北大学药物发现中心(CDD)合作。CDD科学家已经克隆、表达了 和纯化毫克量的NAAA，并开发了基于荧光的药物筛选分析方法 评估。我们还与贝丝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)在溃疡性疾病临床前动物模型中评估我们的化合物 结肠炎。Kokkotou教授还将在体外研究中评估我们的NAAA抑制剂，使用来自 IBD患者在炎性条件下寻求NAAA抑制的早期原则证明 病人。

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.