Developing Recycled Colon Bioavailable (r-CB) COXIBs for the Treatment of Familial adenomatous polyposis (FAP)

摘要： 家族性腺瘤性息肉病（FAP）是一种慢性疾病，如果不及时治疗， 未经治疗。临床试验表明，COXIB（选择性环氧合酶-2抑制剂）， 最初开发用于治疗关节炎的非甾体抗炎药（NSAID）， FAP患者中结直肠癌的发病率。然而，这类药物不能用于临床治疗 FAP由于其严重的全身性副作用，包括不稳定型心绞痛、心肌梗死和心脏病， 血栓制药公司不得不撤回批准的COXIB的化学预防适应症（即， 塞来昔布）从市场上，由于这些严重的副作用。在本申请中，我们建议开发可回收的 结肠生物可利用（r-CB）药物通过靶向肠肝循环将活性COXIB定位在结肠中 (EHC)通过结构修饰，导致低的全身药物暴露和高的结肠药物暴露， 从而在不牺牲其功效的情况下减少全身副作用。在初步研究中，我们 合成了一些化合物，并鉴定了一种（GS 1），其是经历有效EHC的有效考克斯-2抑制剂。 基于这些发现，我们假设考克斯-2抑制剂GS 1可以有效地预防或减缓 在与FAP相关的动物模型中，在低全身暴露的情况下观察结肠癌发生过程。我们的长期 我们的目标是开发高活性的r-CB COXIB，用于预防结肠直肠癌， FAP患者的全身副作用。为了证明r-CB药物的可行性，我们将：（1）评估 使用Pirc大鼠模型的GS1的化学预防功效和全身暴露（Aim 1）;以及（2）鉴定 促进EHC的转运蛋白，并使用细胞培养和/或 动物模型（目标2）。该项目的成功完成将使我们能够证明r-CB药物 只有在结肠中才能被生物利用。这将使选择性治疗或预防 结肠癌而没有严重的全身副作用。此外，该项目将使我们能够产生初步的 用于编制R 01级提案的数据。预计研究界将利用这一点 开发用于治疗其他结肠疾病的药物的方法;特别是与考克斯-2- 介导的结肠癌发生。

Abstract: Familial adenomatous polyposis (FAP) is a chronic disease that predictably leads to colorectal cancer if left untreated. Clinical trials have shown that COXIBs (selective cyclooxygenase-2 inhibitors), a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs) that were originally developed to treat arthritis, effectively reduce the incidence of colorectal cancer in FAP patients. However, this class of drugs cannot be used clinically to treat FAP due to their severe systemic side effects including unstable angina, myocardial infarction, and cardiac thrombus. Drug companies have had to withdraw the chemopreventive indication of approved COXIBs (i.e., celecoxib) from the market due to these serious side effects. In this application, we propose to develop recycled colon bioavailable (r-CB) drugs to localize the active COXIBs in the colon by targeting enterohepatic circulation (EHC) via structure modification, resulting in low systemic drug exposure and high colonic drug exposure, thereby reducing the systemic side effects without sacrificing their efficacy. In the preliminary study, we have synthesized a few compounds and identified one (GS1) that is a potent COX-2 inhibitor undergoing efficient EHC. Based on these findings, we hypothesize that COX-2 inhibitor GS1 can effectively prevent or slow down the process of colon carcinogenesis with low systemic exposure in animal models relevant to FAP. Our long-term goal is to develop highly active r-CB COXIBs for the prevention of colorectal cancer that have limited or no systemic side effects in FAP patients. To prove the feasibility of r-CB drugs, we will: (1) evaluate the chemopreventive efficacy and systemic exposure of GS1 using the Pirc rat model (Aim 1); and (2) identify the transporter(s) facilitating EHC and evaluate the impact of EHC on the drug distribution using cell culture and/or animal models (Aim 2). The successful completion of this project will allow us to demonstrate that r-CB drugs that are only bioavailable in the colon can be created. This would enable selective treatment or prevention of the colonic cancer without severe systemic side effects. In addition, this project will allow us to generate preliminary data for the preparation of an R01-level proposal. It is expected that the research community will use this approach to develop drugs for the treatment of other colonic diseases; especially those related to COX-2- mediated colon carcinogenesis.