Development of orally delivered, non-absorbable AT1 receptor antagonists for infl

描述（由申请人提供）：目前大多数炎症性肠病（IBD）药物治疗的一个主要局限性是这些药物的不分青红皂白的免疫抑制作用。我们最近已经证明了通过阻断肾素-血管紧张素系统的1a型（AT 1a）受体的信号传导，在小鼠葡聚糖硫酸钠（DSS）模型中减轻结肠炎进展的能力。干预导致结肠炎的临床严重程度显著降低，组织学评分改善，促炎细胞因子表达下调。AT 1a受体是触发NF？B级联反应，最终导致细胞凋亡。它也对纤维化形成的起始具有特异性，并且已显示在IBD的DDS模型中选择性过表达。因此，寻求AT 1a受体拮抗剂有可能导致IBD的有效和选择性治疗。虽然这种治疗在治疗IBD方面显示出巨大的潜力，但AT 1a阻断的主要后果是全身性低血压。为了解决这个问题，我们选择了一系列原型药物，这些药物显示出阻断AT 1a受体信号传导的高能力，但显示出较差的肠道通透性。这些原型药物的初步临床前研究表明，当通过经肛门途径递送时，在治疗结肠炎方面具有非常高的疗效，而没有全身血流动力学副作用。由于它们的口服利用度差和它们的强AT 1a受体结合，我们推测这些AT 1a受体拮抗剂将是口服递送的良好候选物。我们建议合成一系列的AT 1a受体拮抗剂，并在基于细胞的测定中测试它们的功效。将使用肠渗透性和生物利用度的标准啮齿动物模型检测这些候选药物沿整个胃肠道的吸收潜力沿着。最后，我们将确定潜在的先导化合物在IBD临床前小鼠模型中的功效。该提案的目标是使用AT 1a拮抗剂开发一种全新类型的IBD药物治疗，其重点是局部控制炎症反应，而没有全身副作用。由于这类药物目前未用于IBD，因此这种方法可能用作单一疗法或添加到当前方案中，从而减少全身免疫抑制。这些研究的结果可能会导致一种治疗炎症性肠病的独特策略。TSRL与密歇根大学的Dan Teitelbaum博士、Scott Larsen博士和Hollis Showalter博士合作解决这个问题。该团队在药物化学，炎症性肠病药理学和口服吸收策略领域为该计划带来了丰富的经验和专业知识。公共卫生相关性：SBIR项目的第一阶段正在寻求开发用于治疗炎症性肠病的新药，炎症性肠病是一种使人衰弱的疾病，目前只能用引起显著副作用的药物治疗。我们的目标是开发一种药物，可以很容易地在疾病爆发以及维持治疗期间口服。

DESCRIPTION (provided by applicant): A major limitation with most current medical therapies for inflammatory bowel disease (IBD) is the indiscriminant immunosuppressive effect of these drugs. We have recently demonstrated the ability to palliate the progression of colitis in a mouse dextran sodium sulfate (DSS) model through blockage of signaling via the type 1a (AT1a) receptor of the renin-angiotensin system. The intervention leads to significant reduction in the clinical severity of colitis, improvement in histologic scores and a down-regulation in the expression of proinflammatory cytokines. The AT1a receptor is a specific receptor which triggers the NF?B cascade, ultimately resulting in apoptosis. It is also specific for the initiation of fibrosis formation and has been shown to be selectively overexpressed in the DDS model of IBD. Hence, pursuing the AT1a receptor antagonists has the potential to result in a potent and selective therapy for IBD. Although this treatment shows tremendous potential in treating IBD, a major consequence of the AT1a blockade is systemic hypotension. To circumvent this problem, we have selected a series of prototype drugs that display a high capacity for blockage of AT1a receptor signaling, but show poor intestinal permeability. Preliminary pre-clinical studies of these prototype drugs demonstrate very high efficacy in the treatment of colitis when delivered via the transanal route, without systemic hemodynamic side-effects. Due to their poor oral availability and their strong AT1a receptor binding, we theorize that these AT1a receptor antagonists would be good candidates for oral delivery. We propose to synthesize a series of AT1a receptor antagonists and test their efficacy in cell based assays. These candidates will be tested for their absorption potential along the entire gastrointestinal tract using standard rodent models of intestinal permeability and bioavailability. Finally, we will determine the efficacy of the potential lead compounds in a preclinical murine model of IBD. The goal of this proposal is to develop an entirely new type of drug therapy for IBD using the AT1a antagonists, which focuses on local control of the inflammatory response, without systemic side effects. Since this class of drugs is not currently used for IBD, this approach potentially could be used as either single therapy, or added to current regimens, allowing for reduced systemic immune suppression. Findings from these studies could lead to a unique strategy to treat inflammatory bowel disease. TSRL has formed a collaboration with Drs. Dan Teitelbaum, Scott Larsen and Hollis Showalter of the University of Michigan to address this problem. The team brings a wealth of experience and expertise in the areas of medicinal chemistry, inflammatory bowel disease pharmacology and oral absorption strategies to the program. PUBLIC HEALTH RELEVANCE: This phase I SBIR project is seeking to develop novel medicines for the treatment of inflammatory bowel disease, a debilitating disease that is currently only treatable with drugs which cause significant side effects. The goal is the development of a medicine that can be easily taken by mouth both during a flare-up of the disease as well as a maintenance treatment.