New Chemical Tools for the Synthesis of Trisubstituted Hydroxylamines and their Application as Bioisosteres in Medicinal Chemistry

合成三取代羟胺的新化学工具及其在药物化学中作为生物等排体的应用

基本信息

批准号：
10349762
负责人：
David Crich
金额：
$ 22.32万
依托单位：
UNIVERSITY OF GEORGIA
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：
2021-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349762
关键词：
Adoption Ames Assay Amides Antihistamines Biological Assay Carbon Cell Line Cells Chemical Structure Chemicals Chemistry Communities Comparative Study Complement Data Databases Development Disease Ethanolamines Ethers Goals HepG2 Human Hydrocarbons Hydrogen Bonding Hydrogen Peroxide Hydroxylamine Industrialization Ligands Literature Liver Microsomes Magnesium Metabolic Metabolic Activation Methods Modeling Mutagens Nitrogen Oxygen Periodicity Peroxides Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Primary carcinoma of the liver cells Property Reaction Reagent Resolution Series Solubility System Thermodynamics Toxic effect Validation Variant alkalinity alkyl group base bioactive natural products carbene comparative cycloaddition drug discovery kalkitoxin lipophilicity marine natural product novel sigma-2 receptor sugar tool tool development

项目摘要

This is a proposal to develop new tools for the practical effective synthesis of N,N,O- trisubstituted hydroxylamines, or hydroxalogs, as novel isosteres for application in medicinal chemistry across a broad swath of compound classes and diseases states. The three specific aims presented encompass i) tools development for the synthesis of N,N,O-trisubstituted hydroxylamines by a variety of inter- and intramolecular methods; ii) synthesis of a series of phenylpropylpiperidine ligands for the σ-1 and σ-2 receptors and their use as models for the comparative study of the physical and drug-like properties of the hydroxalogs, thereby enhancing their applicability as tools in medicinal chemistry; iii) synthesis of a series of hydroxalogs of the ethanolamine H1 antagonists and comparative determination of their antihistamine activity in a cell-based assay, again with the view to validating the hydroxalogs as isosteres as tools in medicinal chemistry.

这是一项提出的建议，用于开发新工具，用于实践有效合成N，N，O- 二碱成立的羟胺或羟基胺作为新颖的等值剂用于应用大量化合物和疾病状态的药物化学反应。提出的三个特定目的包含i）综合工具开发 N，N，O-TRIBSTTETSTUS的羟胺通过多种分子间和分子的方法； ii） σ-1和σ-2受体的一系列苯基丙基哌啶配体的合成以及它们用作对比较研究的模型羟基化，从而增强了它们作为医学化学工具的适用性； iii）乙醇胺H1拮抗剂和在基于细胞的测定中对其抗组胺药活性的比较确定，再次为了将羟基化验证为Isosteres作为医学化学的工具。