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Development of PDE5 Inhibitors for Localized Delivery to Prevent Colorectal Cancer

开发用于局部递送的 PDE5 抑制剂以预防结直肠癌

基本信息

批准号：
10300378
负责人：
Shaobin Miao
金额：
$ 43.93万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300378
关键词：
Affect American Annual Reports Benign Prostatic Hypertrophy Biological Assay Biological Availability Biological Testing Biology Blood Circulation Cancer Patient Cells Cessation of life Chemicals Chemistry Chemoprevention Clinical Colon Carcinoma Colonoscopy Colorectal Cyclic GMP Development Diagnosis Disease Drug Design Drug Industry Drug Interactions Dyspepsia Economics Erectile dysfunction Family Flushing Formulation Gastrointestinal tract structure General Population Geography Goals Headache High Risk Woman High-Risk Cancer Human In Vitro Libraries Malignant Neoplasms Master of Science Methods Mus Myocardial Ischemia National Cancer Institute Nitroglycerin Organ Outcome Pathway interactions Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Polypectomy Population Pre-Clinical Model Predisposing Factor Prevention Procedures Process Pulmonary Hypertension Research Research Project Grants Retrospective cohort Risk Role Science Screening for cancer Solubility Specificity Structure Structure-Activity Relationship Students Testing Time Travel United States Universities Work analog base cancer chemoprevention cancer diagnosis colon cancer prevention colorectal cancer prevention design drug candidate drug development drug discovery epidemiology study gastrointestinal high risk in silico inhibitor/antagonist innovation interest learning outcome men mouse model novel novel therapeutics pre-clinical prevent preventive intervention programs pulmonary arterial hypertension service intervention side effect sildenafil small molecule tadalafil targeted delivery treatment services undergraduate research undergraduate student vardenafil

项目摘要

PROJECT SUMMARY Cancer of the colorectum (CRC) is one of the most common cancers in the world, representing about 8% of all annually reported cancers. Chemoprevention of CRC development is, therefore, a priority for people at high risk, though no drugs are currently available for this unmet clinical need. This work is aimed at developing PDE5 inhibitors (PDE5i) for colon cancer prevention. Novel PDE5i will show fewer side effects than existing PDE5i by designing their polar structural analogs to affect the gut lining while minimizing entrance into the bloodstream. Our strategy is to design novel localized PDE5i’s that remain in the GI tract to specifically target GI diseases. As proof of principle, we have synthesized and tested 2 novel polar analogs of sildenafil: malonyl sildenafil and boronyl-sildenafil. Our central hypothesis is to develop and test new gut localized analogs of sildenafil that have been proven to be effective in colon cancer prevention in preclinical models. Our long-term goal is to develop a family of gut-localized, safe, and effective drugs that can be used for colon cancer prevention. The objective of this proposal is to develop a library of structurally optimized novel chemical entities and determine their efficacy at inhibiting PDE5i in vitro and in mice. The research approaches used in this project will be implemented in the existing Medicinal Chemistry undergraduate program at Augusta University. This project blends the expertise of medicinal chemistry and biology and their roles in early drug discovery. Both the drug design and biological testing reflect the key steps in the pharmaceutical industry workflow for drug development. We will test our hypothesis in this research project by pursuing two specific aims: Specific Aim 1: Develop novel polar analogs of sildenafil for localized delivery and inhibition of PDE5. Specific Aim 2: Develop and test a formulation for the targeted delivery of novel drug candidates. This project is highly innovative and educational in that it merges chemistry and biology during the drug discovery process. This approach corresponds to the student learning outcomes of the Rational Drug Design course, Medicinal Chemistry course, and undergraduate research student courses. This research project will also promote student interest in the master’s program, which offers a Master’s of Science degree in Biomolecular Science. Successful completion of this program will promote drug discovery undergraduate research and result in developing novel drug candidates for colon cancer prevention. Our project outcomes will change the methods, treatments, services, or preventative interventions for patients predisposed to CRC by providing a daily chemoprevention drug as an additional option to the chemoprevention of CRC besides colonoscopies.

项目摘要结直肠癌（CRC）是世界上最常见的癌症之一，约占所有癌症的8%，每年报告的癌症。因此，CRC发展的化学预防是高危人群的优先事项，尽管目前没有药物可用于这种未满足的临床需求。这项工作旨在开发用于预防结肠癌的PDE5抑制剂（PDE5i）。新的PDE5i将显示通过设计它们的极性结构类似物来影响肠道内壁，最大限度地减少进入血液的机会。我们的策略是设计新颖的本地化PDE5i，专门针对胃肠道疾病。作为原理的证明，我们已经合成并测试了2种新的极性化合物，西地那非的类似物：丙二酰西地那非和硼酰西地那非。我们的中心假设是开发和测试新的西地那非的肠道定位类似物已在临床前研究中被证明有效预防结肠癌，模型我们的长期目标是开发一系列肠道定位、安全、有效的药物，来预防结肠癌。该提案的目的是开发一个结构优化的新的化学实体，并确定它们在体外和小鼠中抑制PDE5i的功效。的研究方法本项目中使用的方法将在奥古斯塔现有的药物化学本科课程中实施大学该项目融合了药物化学和生物学的专业知识及其在早期药物治疗中的作用。的发现药物设计和生物测试都反映了制药行业的关键步骤药物开发的工作流程。我们将在本研究项目中通过追求两个具体目标来测试我们的假设：具体目标1：开发西地那非的新型极性类似物，用于局部给药和抑制PDE 5。具体目标2：开发和测试用于靶向递送新型候选药物的制剂。这个项目是高度创新和教育的，因为它在药物发现过程中融合了化学和生物学过程这种方法对应于合理药物设计课程的学生学习成果，药物化学课程和本科研究生课程。该研究项目还将促进学生对硕士课程的兴趣，该课程提供生物分子科学硕士学位科学该项目的成功完成将促进药物发现本科生的研究和成果开发预防结肠癌的新药候选物。我们的项目成果将改变方法，为易患CRC的患者提供治疗、服务或预防性干预，化学预防药物作为结肠镜检查以外的CRC化学预防的额外选择。