Novel Azaborine Derivatives Predicted to Eliminate Acetaminophen Hepatotoxicity

新型氮杂硼啉衍生物有望消除对乙酰氨基酚的肝毒性

• 批准号: 8195745
• 负责人: Shih-Yuan Liu
• 金额: $ 25.44万
• 依托单位: QE CHEMICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2013-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195745
• 关键词: Accident and Emergency department; Accounting; Acetaminophen; Acute Liver Failure; Biological; Biological Testing; Boron; Cell Respiration; Cessation of life; Dose; Drug Kinetics; Drug usage; Evaluation; Event; Exhibits; Fever; Goals; Hepatotoxicity; Human Cell Line; Hypersensitivity; In Vitro; Investigation; Liver; Liver Failure; Metabolic; Methods; N-acetyl-4-benzoquinoneimine; Names; Nitrogen; Overdose; Pain; Pair Bond; Pharmaceutical Preparations; Phase; Phenacetin; Poisoning; Property; Schedule; Scheme; Small Business Technology Transfer Research; Task Performances; Therapeutic Index; Toxic effect; Tylenol; Visit; acetaminophen overdose; analog; base; cytotoxic; cytotoxicity; design; dosage; drug candidate; in vitro testing; novel; phase 2 study; research study

DESCRIPTION (provided by applicant): Overdose on acetaminophen (more commonly known by the brand name Tylenol(R)), accounts for 56,000 emergency room visits and more than 450 deaths annually in the USA. Acetaminophen overdose can occur by a single event of exceeding the recommended daily dosage. Overdose on acetaminophen is facilitated by the fact that it is a common ingredient in over-the-counter medications for cold, allergies, and congestion, conditions for which people often take multiple medications. The hepatotoxicity of acetaminophen is due to N-acetyl-p- benzoquinoneimine (NAPQI), which is generated by oxidative metabolism. Proposed herein are new 1,2-azaborines, wherein a CC bond pair of an arene is replaced with an isosteric boron- nitrogen unit that is designed to eliminate the formation of the toxic metabolite. This proposal seeks to: 1) synthesize novel 1,2-azaborine-based derivatives of acetaminophen, 2) determine their cytotoxicity and pharmacokinetics via appropriate in vitro tests, and 3) identify compounds to be studied in a Phase II STTR application. PUBLIC HEALTH RELEVANCE: Novel Azaborine Derivatives Predicted to Eliminate Acetaminophen Hepatotoxicity Overdose on acetaminophen (more commonly known by the brand name Tylenol(R)), accounts for 56,000 emergency room visits and more than 450 deaths annually in the USA. The toxicity of acetaminophen to the liver is due to a metabolic by-product. Proposed herein are new boron-nitrogen-containing analogues of acetaminophen that are designed to eliminate the formation of that metabolic by-product.

描述（由申请人提供）：在美国，过量服用对乙酰氨基酚（更常见的品牌名称是 Tylenol(R)）每年导致 56,000 例急诊室就诊和 450 多人死亡。对乙酰氨基酚过量可能是由于单一事件超过推荐的每日剂量而发生的。对乙酰氨基酚是治疗感冒、过敏和充血的非处方药物中的常见成分，人们经常服用多种药物来治疗这些疾病，这导致了过量服用对乙酰氨基酚。对乙酰氨基酚的肝毒性是由氧化代谢产生的 N-乙酰基-对苯醌亚胺 (NAPQI) 引起的。本文提出了新的1,2-氮杂硼烷，其中芳烃的CC键对被等排硼-氮单元取代，其旨在消除有毒代谢物的形成。该提案旨在：1) 合成基于 1,2-氮杂硼啉的新型对乙酰氨基酚衍生物，2) 通过适当的体外测试确定其细胞毒性和药代动力学，以及 3) 确定在 II 期 STTR 应用中要研究的化合物。 公共健康相关性：新型氮硼烷衍生物预计可消除对乙酰氨基酚的肝毒性 在美国，过量服用对乙酰氨基酚（更常见的品牌名称是 Tylenol(R)）每年会导致 56,000 例急诊室就诊和 450 多人死亡。对乙酰氨基酚对肝脏的毒性是由于代谢副产物造成的。本文提出了新的对乙酰氨基酚的含硼氮类似物，其旨在消除该代谢副产物的形成。