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

开发口服不可吸收 AT1 受体拮抗剂治疗感染

• 批准号: 7670009
• 负责人: John M Hilfinger
• 金额: $ 26.86万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670009
• 关键词: Address; Adverse effects; Angiotensin II; Apoptosis; Area; Biological Assay; Biological Availability; Cells; Characteristics; Clinical; Colitis; Collaborations; Development; Disease; Dose; Down-Regulation; Ensure; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epithelial Cells; Evaluation; Fibrosis; Flare; Gastrointestinal tract structure; Goals; Histologic; Hypotension; Immune; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intervention; Intestinal Absorption; Intestines; Laboratories; Lead; Losartan; Maintenance; Medical; Medicine; Michigan; Modeling; Mus; Oral; Oral cavity; Outcome; Peptidyl-Dipeptidase A; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Pre-Clinical Model; Receptor Signaling; Renin-Angiotensin System; Rodent Model; Route; Series; Severities; Signal Transduction; Site; Small Business Innovation Research Grant; Sodium Dextran Sulfate; Testing; Therapeutic; Treatment Protocols; Universities; absorption; analog; base; cytokine; design; experience; gastrointestinal; hemodynamics; improved; in vivo; mouse model; novel; overexpression; pre-clinical; preclinical study; programs; prototype; public health relevance; receptor; receptor binding; treatment effect; uptake

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.

描述（由申请人提供）：目前大多数炎症性肠病（IBD）药物疗法的一个主要限制是这些药物的不加区别的免疫抑制作用。我们最近在小鼠右旋糖酐硫酸钠 (DSS) 模型中证明了通过阻断肾素-血管紧张素系统 1a 型 (AT1a) 受体信号传导来缓解结肠炎进展的能力。该干预措施可显着降低结肠炎的临床严重程度、改善组织学评分以及下调促炎细胞因子的表达。 AT1a 受体是一种特异性受体，可触发 NFκB 级联反应，最终导致细胞凋亡。它对于纤维化形成的起始也具有特异性，并且已被证明在 IBD 的 DDS 模型中选择性过表达。因此，寻找 AT1a 受体拮抗剂有可能为 IBD 提供有效的选择性治疗。尽管这种疗法在治疗 IBD 方面显示出巨大潜力，但 AT1a 阻断的一个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，它们对 AT1a 受体信号传导具有很高的阻断能力，但肠道通透性较差。这些原型药物的初步临床前研究表明，通过经肛门途径给药时，在治疗结肠炎方面具有非常高的疗效，且没有全身血流动力学副作用。由于其口服利用度差且 AT1a 受体结合力强，我们推测这些 AT1a 受体拮抗剂将是口服给药的良好候选药物。我们建议合成一系列 AT1a 受体拮抗剂并在基于细胞的测定中测试它们的功效。将使用肠道渗透性和生物利用度的标准啮齿动物模型测试这些候选药物在整个胃肠道的吸收潜力。最后，我们将确定潜在先导化合物在 IBD 临床前小鼠模型中的功效。该提案的目标是使用 AT1a 拮抗剂开发一种全新的 IBD 药物疗法，重点是局部控制炎症反应，且无全身副作用。由于此类药物目前尚未用于治疗 IBD，因此这种方法可能可用作单一疗法，或添加到当前的治疗方案中，从而减少全身免疫抑制。这些研究的结果可能会导致治疗炎症性肠病的独特策略。 TSRL 已与 Drs 建立了合作关系。密歇根大学的 Dan Teitelbaum、Scott Larsen 和 Hollis Showalter 致力于解决这个问题。该团队为该项目带来了药物化学、炎症性肠病药理学和口服吸收策略领域的丰富经验和专业知识。公共健康相关性：第一阶段 SBIR 项目正在寻求开发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，目前只能用会引起严重副作用的药物来治疗。目标是开发一种在疾病发作和维持治疗期间都可以轻松口服的药物。