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

• 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
• 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

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.

项目概要 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% 因此，每年报告的癌症的化学预防是高危人群的首要任务。 尽管目前还没有药物可以满足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)，新型 PDE5i 将展示。 通过设计其极性结构类似物来影响肠道内壁，比现有的 PDE5i 副作用更少，同时 我们的策略是设计保留在血液中的新型本地化 PDE5i。 胃肠道专门针对胃肠道疾病作为原理证明，我们合成并测试了 2 种极地小说。 西地那非的类似物：丙二酰西地那非和硼基西地那非。我们的中心假设是开发和测试新的。 西地那非肠道局部类似物已被证明在临床前预防结肠癌方面有效 我们的长期目标是开发一系列可用于肠道的、安全且有效的药物。 该提案的目的是开发一个结构优化的新化合物库。 化学实体并确定其在体外和小鼠体内抑制 PDE5i 的功效。 该项目中使用的内容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中的作用。 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。 我们将通过追求两个具体目标来检验我们在本研究项目中的假设： 具体目标 1：开发西地那非的新型极性类似物，用于 PDE5 的局部递送和抑制。 具体目标 2：开发并测试一种用于靶向递送新候选药物的制剂。 该项目具有高度创新性和教育意义，因为它在药物发现过程中融合了化学和生物学 这种方法对应于理性药物设计课程的学生学习成果， 该研究项目还将包括药物化学课程和本科生课程。 提高学生对硕士课程的兴趣，该课程提供生物分子理学硕士学位 科学。该计划的成功完成将促进药物发现本科生的研究和成果。 在开发预防结肠癌的新候选药物方面，我们的项目成果将改变方法， 为易患 CRC 的患者提供每日治疗、服务或预防性干预 除结肠镜检查外，化学预防药物作为结直肠癌化学预防的另一种选择。

项目成果

A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice.

• DOI: 10.3390/ijms24119397
• 发表时间: 2023-05-28
• 期刊: International journal of molecular sciences
• 影响因子: 5.6