Development of the orally delivered, non-absorbable ACE inhibitor enalaprilat for

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限制是这些药物不加区别的免疫抑制作用。我们最近在小鼠葡聚糖硫酸钠(DSS)模型中证明了通过抑制肾素-血管紧张素系统中的血管紧张素转换酶(ACE)来阻断信号，从而减轻结肠炎进展的能力。该干预导致结肠炎的临床严重程度显著降低，组织学评分提高，促炎症细胞因子的表达下调。血管紧张素转换酶催化血管紧张素I转化为血管紧张素II，进而触发核因子：B级联反应，最终导致细胞凋亡。血管紧张素II也参与了纤维化的形成。因此，寻找有效的血管紧张素转换酶抑制剂，如依那普利拉，有可能导致IBD的有效和选择性治疗。尽管这种治疗方法在治疗IBD方面显示出巨大的潜力，但ACE抑制的一个主要后果是目前市场上销售的大多数口服ACE抑制剂出现全身性低血压。然而，依那普利拉是一种静脉制剂，因为它表现出较差的口服吸收，这一特点非常适合局部治疗IBD。初步的临床前研究表明，依那普利拉经肛门给药治疗结肠炎非常有效，没有全身血流动力学副作用。由于依那普利拉口服利用度差，抗血管紧张素转换酶活性强，我们推测依那普利拉是一种理想的口服给药方案。我们建议对依那普利拉在疾病和健康小鼠整个胃肠道的吸收潜力进行表征，以确定简单的口服片剂剂量是否可以作为依那普利拉治疗溃疡性结肠炎和克罗恩病的可行策略。最后，我们将确定依那普利拉在临床前IBD小鼠模型中的疗效。这项提议的目标是开发一种全新的治疗IBD的药物疗法，使用现有的、已被证明安全的治疗方法，并专注于局部控制炎症反应，而不产生全身副作用。由于这类药物目前不用于IBD，这种方法可能被用作单一疗法，或添加到当前的方案中，从而减少全身免疫抑制。这些研究的发现可能导致一种独特的治疗炎症性肠病的策略。TSRL已经与密歇根大学的Dan Teitelbaum博士建立了合作关系来解决这个问题。该团队在炎症性肠病、药理学和口服吸收策略方面为该计划带来了丰富的经验和专业知识。 公共卫生相关性：该第一阶段SBIR项目正在寻求开发一种现有的降压药物，用于另一种适应症，即炎症性肠病的治疗。炎症性肠病是一种衰弱的疾病，目前只能用会产生显著副作用的药物来治疗。我们的目标是开发一种被证明安全的药物，既可以在疾病突发期间轻松口服，也可以在维持治疗中使用。

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 inhibition of the angiotensin-converting enzyme (ACE) in 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 pro-inflammatory cytokines. The ACE enzyme catalyzes the conversion of angiotensin I to angiotensin II, which in turn triggers the NF:B cascade, ultimately resulting in apoptosis. Angiotensin II is also involved in the initiation of fibrosis formation. Hence, pursuing potent inhibitors of ACE, such as enalaprilat, 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 ACE inhibition is systemic hypotension seen with most currently marketed oral ACE inhibitors. Enalaprilat, however, is marketed as an intravenous formulation, since it shows poor oral absorption, a characteristic that is highly desirable for the local treatment of IBD. Preliminary pre-clinical studies with enalaprilat demonstrate very high efficacy in the treatment of colitis when delivered via the trans-anal route, without systemic hemodynamic side-effects. Due to its poor oral availability and strong potency against ACE, we hypothesize that enalaprilat is an ideal candidate for oral delivery. We propose to characterize enalaprilat's absorption potential along the entire gastrointestinal tract in diseased and healthy mice to determine if simple oral tablet dosing could be a feasible delivery strategy for enalaprilat for both ulcerative colitis as well as Crohn's disease. Finally, we will determine the efficacy of enalaprilat in preclinical murine models of IBD. The goal of this proposal is to develop an entirely new type of drug therapy for IBD using an existing, proven safe therapeutic, and focusing 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 a 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 collaboration with Dr. Dan Teitelbaum of the University of Michigan to address this problem. The team brings a wealth of experience and expertise in the areas of inflammatory bowel disease pharmacology and oral absorption strategies to the program. PUBLIC HEALTH RELEVANCE: This phase I SBIR project is seeking to develop an existing antihypertensive medicine for an additional indication, the treatment of inflammatory bowel disease. Inflammatory bowel disease is a debilitating disease that is currently only treatable with drugs which cause significant side effects. The goal is the development of a medicine with proven safety that can be easily taken by mouth both during a flare-up of the disease as well as a maintenance treatment.