Treatment of Inflammatory Bowel Disease with Ceramidase Inhibitors

描述(申请人提供)：该计划的目标是开发新型的人中性神经酰胺酶抑制剂(ASAH2)，作为炎症性肠病(IBD)的有效治疗剂。鞘磷脂被越来越多地认为是炎症的关键介质，并被认为介导促炎细胞因子的作用，如肿瘤坏死因子？？(肿瘤坏死因子？)这些在IBD中具有核心重要性。越来越多的证据表明，胃肠上皮和内皮细胞内的鞘氨醇-1-磷酸(S1P)是由神经鞘磷脂酶、中性神经酰胺酶和鞘氨醇激酶共同作用产生的，推动了IBD的炎症过程。因此，鞘磷脂代谢酶是开发治疗IBD新药的潜在分子靶点。由于神经酰胺酶在调节炎症中的关键作用，Apogee生物技术公司正在开发神经酰胺酶抑制剂来治疗炎症性疾病。我们已经鉴定出人类ASAH2的第一种非脂类药物，它是人类胃肠道表达的主要神经酰胺酶同工酶。在这一阶段的SBIR项目中，我们将通过以下特定目的在两个IBD体内模型中评价三种新型神经酰胺酶抑制剂(代表目前正在优化的三种神经酰胺酶抑制剂)的药理和抗IBD活性：1.合成并评价新型神经酰胺酶抑制剂的毒性和药代动力学。我们通过高通量筛选和药物化学鉴定了三种化学类型的类药物神经酰胺酶抑制剂。这些化学类型中每种类型的先导化合物将以克数合成，用于体内测试。将确定每种神经酰胺酶抑制剂的最大耐受量和药代动力学，以优化IBD模型中的治疗方案。2.评价神经酰胺酶抑制剂在DSS溃疡性结肠炎模型中的治疗作用。每种新型神经酰胺酶抑制剂都将在葡聚糖硫酸钠(DSS)小鼠溃疡性结肠炎模型中进行有效性测试，使用临床、形态和生化终点。3.评价神经酰胺酶抑制剂在克罗恩病TNBS模型中的治疗效果。这三种新型神经酰胺酶抑制剂的有效性将在克罗恩病小鼠的TNBS模型中进行检验，使用与目标2类似的评估终点。这项工作将首次在广泛使用的IBD模型中提供神经酰胺酶抑制剂的原理有效性研究。我们在建议的IBD模型方面拥有丰富的经验，并在将鞘磷脂靶向药物引入临床试验方面有着良好的记录。我们相信，使用中性神经酰胺酶抑制剂治疗IBD是一种创新的方法，有可能迅速推广到临床。 公共卫生相关性：根据疾病控制和预防中心的数据，美国IBD的发病率估计为140万人，总体医疗成本超过17亿美元。这种慢性疾病无法治愈，通常需要终生护理。从长远来看，高达75%的克罗恩病患者和25%的溃疡性结肠炎患者将需要手术，这表明需要新的治疗方法。广泛的工作，包括我们的初步研究，表明抑制中性神经酰胺酶可能为这些疾病提供一种新的治疗方法。拟议的研究将为这一假设提供第一个检验。

DESCRIPTION (provided by applicant): The goal of this program is to develop novel inhibitors of human neutral ceramidase (ASAH2) that are effective as therapeutic agents for Inflammatory Bowel Diseases (IBDs). Sphingolipids are being increasingly recognized as key mediators of inflammation, and are known to mediate the effects of pro-inflammatory cytokines such as tumor necrosis factor-? (TNF?) that are of central importance in IBD. Accumulating evidence demonstrates that sphingosine-1-phosphate (S1P) produced by the combined action of sphingomyelinases, neutral ceramidase and sphingosine kinases within gastrointestinal epithelial and endothelial cells drives the inflammation processes in IBD. Therefore, sphingolipid metabolizing enzymes are potential molecular targets for the development of new drugs for the treatment of IBDs. Because of the pivotal role of ceramidases in regulating inflammation, Apogee Biotechnology Corporation is developing ceramidase inhibitors to treat inflammatory diseases. We have identified the first non-lipid, i.e. "drug-like", inhibitors of human ASAH2, which is the dominant ceramidase isozyme expressed in the human gastrointestinal tract. In this Phase 1 SBIR project, we will evaluate the pharmacology and anti-IBD activity of three novel ceramidase inhibitors (representing three chemotypes of ceramidase inhibitors currently being optimized) in two in vivo models of IBD through the following Specific Aims: 1. To synthesize and evaluate the toxicity and pharmacokinetics of novel ceramidase inhibitors. We have identified three chemotypes of drug-like ceramidase inhibitors by high-throughput screening and medicinal chemistry. The lead compound within each of these chemotypes will be synthesized in gram quantities for in vivo testing. The Maximum Tolerated Dose and pharmacokinetics of each of these ceramidse inhibitors will be determined to optimize treatment protocols in the IBD models. 2. To evaluate the therapeutic efficacies of ceramidase inhibitors in the DSS model of ulcerative colitis. Each of the novel ceramidase inhibitors will be tested for efficacy in the dextran sulfate sodium (DSS) model of ulcerative colitis in mice, using a combination of clinical, morphological and biochemical endpoints. 3. To evaluate the therapeutic efficacies of ceramidase inhibitors in the TNBS model of Crohn's Disease. The efficacies of the three novel ceramidase inhibitors will be examined in the TNBS model of Crohn's disease in mice, utilizing similar evaluation endpoints as in Aim 2. This work will provide the first proof-of-principle efficacy studies of ceramidase inhibitors in widely- utilized models of IBD. We have extensive experience with the proposed IBD models and a proven track record for bringing sphingolipid-targeted drugs into clinical trials. We believe that the use of neutral ceramidase inhibitors for te treatment of IBD is an innovative approach that is likely to be rapidly translated to the clinic. PUBLIC HEALTH RELEVANCE: According to the Centers for Disease Control and Prevention, the estimated incidence of IBD in the US is 1.4 million persons, with an overall health care cost of more than $1.7 billion. This chronic condition is without a medical cure and commonly requires a lifetime of care. Over the long term, up to 75% of patients with Crohn's disease and 25% of those with ulcerative colitis will require surgery, making it clear that new therapeutic approaches are needed. Extensive work, including our Preliminary Studies, suggests that inhibition of neutral ceramidase may provide a new therapy for these diseases. The proposed studies will provide the first test of this hypothesis.