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Enhancing Physicochemical Properties through Synthesis and Formulation of Piclamilast- and Lapatinib-Derived Analogs.

机译：通过合成和配制Piclamilast和Lapatinib衍生的类似物来增强理化性质。

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摘要

Human African trypanosomiasis (HAT) is a neglected tropical disease of significant morbidity and mortality in sub-Saharan Africa. Current chemotherapeutics targeting the causative agent Trypanosoma brucei lack oral bioavailability, efficacy, and safety. New small molecule drugs are desperately needed for HAT. Target repurposing represents one method for rapidly discovering new anti-trypanosomal compounds. This concept has been applied to repurposing small molecule inhibitors of human phosphodiesterases (PDEs) and protein tyrosine kinases (PTKs) for HAT, while improving physicochemical properties.;The first project in this dissertation begins with the human PDE4 inhibitor piclamilast, which has an IC50 value of 4.7 microM against T. brucei PDEB1. Based upon this scaffold, new analogs were designed, synthesized, and screened for their biological activity against TbrPDEB1. Secondly, previous optimization of the human tyrosine kinase inhibitor lapatinib led to the discovery of the 4-anilino-quinazoline NEU-617, a potent (EC 50 = 42 nM) antitrypanosomal agent. Since alkynyl thienopyrimidines are well-known scaffolds for tyrosine kinase inhibitors, we assessed this scaffold as an alternative to the quinazoline of NEU-617. In addition, analogs of the NEU-617 were designed and synthesized to improve their physicochemical properties, such as lipophilicity and predicted central nervous system penetration. Lastly, nanoformulations have been shown to improve the oral bioavailability and circulation half-life of their encapsulated drug components. Because of this, nanoemulsions, liposomes, and polymeric nanoparticles were explored for their potential parasitic inhibitory effects and their ability to improve the physicochemical properties of NEU-617.
机译：人类非洲锥虫病（HAT）是被忽视的热带病，在撒哈拉以南非洲地区具有很高的发病率和死亡率。当前针对病原体布鲁氏锥虫的化学疗法缺乏口服生物利用度，功效和安全性。 HAT急需新的小分子药物。目标重用代表了一种快速发现新的抗锥虫化合物的方法。该概念已被应用于人类磷酸二酯酶（PDEs）和蛋白质酪氨酸激酶（PTKs）的小分子抑制剂对HAT的再利用，同时改善了其理化性质。本论文的第一个项目始于人类PDE4抑制剂piclamilast，其IC50为50。 T. brucei PDEB1为4.7 microM。基于该支架，设计，合成并筛选了针对TbrPDEB1的生物活性的新类似物。其次，先前对人酪氨酸激酶抑制剂拉帕替尼的优化导致了4-苯胺基-喹唑啉NEU-617的发现，这是一种有效的（EC 50 = 42 nM）抗锥虫病药物。由于炔基硫代嘧啶是酪氨酸激酶抑制剂的众所周知的支架，因此我们评估了该支架作为NEU-617喹唑啉的替代物。此外，还设计并合成了NEU-617的类似物以改善其理化性质，例如亲脂性和预测的中枢神经系统渗透。最后，已证明纳米制剂可改善其胶囊化药物组分的口服生物利用度和循环半衰期。因此，人们对纳米乳剂，脂质体和聚合物纳米颗粒的潜在寄生虫抑制作用及其改善NEU-617物理化学特性的能力进行了研究。

著录项

  • 作者

    Woodring, Jennifer L.;

  • 作者单位

    Northeastern University.;

  • 授予单位 Northeastern University.;
  • 学科 Chemistry Biochemistry.;Biology Cell.;Nanoscience.;Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 332 p.
  • 总页数 332
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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