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）：对对乙酰氨基酚的用药过量（更常见于品牌Tylenol（R）），占56,000次急诊室就诊，每年在美国每年有450多人死亡。对乙酰氨基酚的过量可以通过超过建议的每日剂量的单一事件发生。对对乙酰氨基酚的过量用药是由于人们经常服用多种药物的寒冷，过敏和拥塞而促进了以下事实。对乙酰氨基酚的肝毒性是由于N-乙酰基-P-苯甲酰酮（NAPQI）引起的，这是由氧化代谢产生的。本文提出的是新的1,2-azaborines，其中一对芳烃的CC键对被同分性硼氮单位代替，旨在消除有毒代谢物的形成。该提案试图：1）合成对乙酰氨基酚的新型1,2-亚恰当基衍生物，2）通过适当的体外测试确定其细胞毒性和药代动力学，3）鉴定化合物在II期STTR应用中研究。 公共卫生相关性：预计将消除对乙酰氨基酚对乙酰氨基酚肝毒性过量的新型阿Zaborine衍生物（更常见的是tylenol品牌（R），占56,000个急诊室就诊，在美国每年有450多人死亡。对乙酰氨基酚对肝脏的毒性是由于代谢副产品引起的。本文提出的是对乙酰氨基酚的新型含硼氮的类似物，旨在消除该代谢副产品的形成。