Novel Azaborine Derivatives Predicted to Eliminate Acetaminophen Hepatotoxicity

描述（由申请人提供）：过量服用对乙酰氨基酚（通常以品牌名称泰诺(R)而闻名），在美国每年造成56,000次急诊室就诊和450多人死亡。对乙酰氨基酚过量可由超过每日推荐剂量的单一事件引起。对乙酰氨基酚是治疗感冒、过敏和充血的非处方药物中的一种常见成分，这一事实助长了对乙酰氨基酚的过量使用，而人们通常会服用多种药物。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。本文提出了一种新的1,2-氮杂aborines，其中芳烃的CC键对被等构硼氮单元取代，旨在消除有毒代谢物的形成。本提案旨在：1)合成新型的1,2-氮杂波碱对乙酰氨基酚衍生物，2)通过适当的体外试验确定其细胞毒性和药代动力学，以及3)确定用于II期STTR应用研究的化合物。

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.