Chemistry principles applied to the development of new catalytic C-H bond functionalization methods for amine and heterocycle preparation and to the design, synthesis and use of new enzyme inhibitors

化学原理应用于胺和杂环制备的新型催化C-H键功能化方法的开发以及新型酶抑制剂的设计、合成和使用

• 批准号: 9910428
• 负责人: JONATHAN A ELLMAN
• 金额: $ 73.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910428
• 关键词: Alcohols; Alzheimer' s Disease; Amines; Carbon; Cathepsins; Chagas Disease; Chemicals; Chemistry; Complex; Corpus striatum structure; Development; Dihydropyridines; Enzyme Inhibitor Drugs; Enzymes; Frequencies; Human; Hydrogen Bonding; Impaired cognition; In Situ; Isoenzymes; Methods; Neurodegenerative Disorders; Nitrogen; Oral; Parasites; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Phosphoric Monoester Hydrolases; Physiological; Planet Earth; Post-Translational Protein Processing; Preparation; Protein Tyrosine Phosphatase; Protein-arginine deiminase; Regulation; Roentgen Rays; Role; Structure; analog; base; c new; catalyst; cost; cruzain; design; drug discovery; drug production; functional group; in vivo imaging; inhibitor/antagonist; innovation; mouse model; phosphatase inhibitor; piperidine; small molecule; small molecule inhibitor; wasting

Project Summary/Abstract The discovery and development of new methods for the preparation and use of organic compounds has considerable impact upon how drugs are discovered and synthesized. One overall objective of this application is the development of catalytic C-H bond activation and carbon-carbon bond formation for the convergent assembly of amine containing compounds present in 84% of small-molecule drugs. Methods for the preparation of the subset of nitrogen heterocycles present in 59% of drugs are emphasized. Efficient syntheses of these compound classes will be accomplished by C-H functionalization methods. One example is stereoselective, catalytic two- and three-component C-H bond additions to C=O/C=N bonds to provide diverse amine and alcohol products that in situ can be transformed into more complex, drug-relevant heterocycles. New earth abundant Co(III) catalysts will be developed and studied for these transformations. Another example is efficient syntheses of diverse piperidines, the heterocycle class with the highest frequency of occurrence in drugs, by regio- and stereoselective elaboration of highly substituted 1,2-dihydropyridines generated in situ by one step C-H bond functionalization/electrocyclization cascades. New methods will also be achieved to prepare bridged and fused bicyclic and multicyclic piperidines, including pharmaceutical agents. Innovative new types of reactivity will be explored in C-H bond functionalization and subsequent transformations. These significant studies will enable the more rapid preparation of analogs in drug discovery efforts and reduced cost and waste in drug production due to; (1) the ubiquitous presence of C-H bonds in organic compounds, (2) the very high functional group compatibility of the Rh and Co catalysts used, and (3) the importance of the compound classes prepared. The second overriding objective is the development and use of potent and selective enzyme inhibitors discovered through substrate-based fragment approaches. Orally available inhibitors of cruzain, an essential protease of the parasite responsible for Chagas disease, have been developed as have near-IR quenched activity-based inhibitors of cathepsin S for imaging in vivo. The first inhibitors of Striatal-Enriched Phosphatase (STEP), a protein tyrosine phosphatase (PTP) implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), will be advanced. Structure- based optimization will be carried out using the first x-ray structures of STEP inhibitor complexes. Reversible covalent inhibitors developed to recapitulate known physiological means of PTP regulation will also be advanced. This innovative platform for PTP inhibition has already resulted in compounds that reverse cognitive dysfunction in AD mouse models. The substrate fragment approach will also be applied to the increasingly prominent class of protein post-translational modification enzymes, the protein arginine deiminases (PADs), for which little inhibitor development has so far been carried out. This new and innovative approach has already resulted in PAD3 selective small molecule inhibitors and will be applied to the other PAD isozymes.

项目摘要/摘要 用于制备和使用有机化合物的新方法的发现和开发具有 对如何发现和合成药物的影响很大。该应用程序的总体目标一个 是催化C-H键激活和碳碳键形成的发展 84％的小分子药物中含有胺的胺的组装。该方法 强调了59％的药物中存在的氮杂环的子集的制备。有效的合成 这些化合物类别将通过C-H功能化方法完成。一个例子是 立体选择性，催化两分和三分量的C-H键在C = O/C = N键中添加多种多样 原位的胺和酒精产品可以转化为更复杂的，与药物相关的杂环。 将开发并研究新地球丰富的CO（III）催化剂。其他 示例是有效的哌啶的合成，是最高频率的杂环类 药物的发生，通过高度取代的1,2-二氢吡啶的区域和立体选择性阐述 由一个步骤C-H键官能化/电囊化级联反应产生。新方法也将是 可以准备桥接和融合的双环和多环状哌啶，包括药物。 创新的新型反应性将在C-H键功能中探索，随后进行 转型。这些重大研究将使在药物发现中更快地制备类似物 努力，减少因药物生产的成本和浪费； （1）无处不在的C-H键 有机化合物，（2）使用的RH和CO催化剂的功能组兼容性非常高，（3） 准备的复合类的重要性。第二个重要目标是发展和 通过基于底物碎片方法发现的有效酶抑制剂的使用。口头 Cruzain的可用抑制剂，Cruzain是负责Chagas疾病的寄生虫的必要蛋白酶 开发为在体内成像的近红外活性基于活性的抑制剂。第一个 富含纹状体的磷酸酶的抑制剂（步骤），蛋白酪氨酸磷酸酶（PTP）与A有关 包括阿尔茨海默氏病（AD）在内的神经退行性疾病的数量将得到病情。结构- 将使用步骤抑制剂复合物的第一个X射线结构进行基于优化。可逆 为了概括已知的PTP调节生理手段而开发的共价抑制剂也将是 先进的。这种用于PTP抑制的创新平台已经导致了逆转认知的化合物 AD鼠标模型中的功能障碍。底物碎片方法也将应用于越来越多的 蛋白质后翻译后修饰酶的突出类别，蛋白精氨酸脱氨酸酶（PADS），用于 到目前为止，几乎没有抑制剂开发。这种新的创新方法已经 导致PAD3选择性小分子抑制剂，并将应用于其他PAD同工酶。