Treatment of Inflammatory Bowel Disease with Ceramidase Inhibitors

描述（由申请人提供）：本项目的目标是开发新型人中性神经酰胺酶（ASAH 2）抑制剂，其可有效作为炎症性肠病（IBD）的治疗药物。鞘脂被越来越多地认为是炎症的关键介质，并已知介导促炎细胞因子如肿瘤坏死因子-β 1的作用。(TNF?)这对IBD至关重要。越来越多的证据表明，鞘氨醇-1-磷酸（S1 P）由鞘磷脂酶，中性神经酰胺酶和鞘氨醇激酶在胃肠上皮和内皮细胞内的联合作用产生，驱动IBD的炎症过程。因此，鞘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。我们已经确定了第一个非脂质，即“药物样”，抑制剂的人ASAH 2，这是占主导地位的神经酰胺酶同工酶在人胃肠道中表达。在该1期SBIR项目中，我们将通过以下特定目的在IBD的两种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神经酰胺酶抑制剂的三种化学型）的药理学和抗IBD活性：合成新型神经酰胺酶抑制剂并评价其毒性和药代动力学。我们通过高通量筛选和药物化学方法鉴定了三种药物样神经酰胺酶抑制剂的化学类型。这些化学型中的每一种内的先导化合物将以克的量合成用于体内测试。将确定每种神经酰胺酶抑制剂的最大耐受剂量和药代动力学，以优化IBD模型中的治疗方案。 2.评价神经酰胺酶抑制剂在溃疡性结肠炎DSS模型中的治疗效果。将使用临床、形态学和生物化学终点的组合，在小鼠溃疡性结肠炎的葡聚糖硫酸钠（DSS）模型中测试每种新型神经酰胺酶抑制剂的功效。 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。三种新型神经酰胺酶抑制剂的功效将在小鼠克罗恩病TNBS模型中进行检查，使用与目标2中相似的评价终点。 这项工作将提供神经酰胺酶抑制剂在广泛使用的IBD模型中的第一个原理验证有效性研究。我们在所提出的IBD模型方面拥有丰富的经验，并在将鞘脂靶向药物纳入临床试验方面拥有良好的记录。我们相信，中性神经酰胺酶抑制剂治疗IBD是一种创新的方法，有可能迅速转化为临床。 公共卫生相关性：根据疾病控制和预防中心的数据，美国IBD的估计发病率为140万人，总体医疗费用超过17亿美元。这种慢性疾病是没有医疗治愈，通常需要一生的照顾。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。包括我们的初步研究在内的大量工作表明，抑制中性神经酰胺酶可能为这些疾病提供新的治疗方法。拟议中的研究将为这一假设提供第一次检验。

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.