Novel Azaborine Derivatives Predicted to Eliminate Acetaminophen Hepatotoxicity

描述（由申请人提供）：在美国，对乙酰氨基酚（更常见的品牌名称Tylenol（R））过量导致56，000例急诊室就诊和450多例死亡。对乙酰氨基酚过量可通过超过推荐每日剂量的单一事件发生。过量服用对乙酰氨基酚是因为它是治疗感冒、过敏和充血的非处方药的常见成分，人们经常服用多种药物。对乙酰氨基酚的肝毒性是由于氧化代谢产生的N-乙酰基-对-苯醌亚胺（NAPQI）。本文提出了新的1，2-氮杂硼杂环，其中芳烃的CC键对被设计为消除毒性代谢物的形成的电子等排硼-氮单元替代。这项建议旨在：1）合成新的基于1，2-氮杂硼杂环的对乙酰氨基酚衍生物，2）通过适当的体外试验测定它们的细胞毒性和药代动力学，和3）鉴定在II期STTR应用中待研究的化合物。 公共卫生相关性：新的氮杂硼衍生物预计将消除对乙酰氨基酚肝毒性对乙酰氨基酚（更常见的品牌名称泰诺（R））过量，占56,000急诊室访问和超过450人死亡，每年在美国。对乙酰氨基酚对肝脏的毒性是由于代谢副产物。本文提出了新的含硼-氮的对乙酰氨基酚类似物，其被设计用于消除该代谢副产物的形成。

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.