Novel Azaborine Derivatives Predicted to Eliminate Acetaminophen Hepatotoxicity

描述(由申请人提供)：服用过量的对乙酰氨基酚(更为人熟知的品牌名称是泰诺(R))，在美国每年导致56000例急诊室就诊和450多例死亡。超过每日推荐剂量的单一事件可导致扑热息痛过量。扑热息痛是治疗感冒、过敏和充血的非处方药中的常见成分，人们经常服用多种药物，这一事实促进了对乙酰氨基酚的过量服用。对乙酰氨基酚的肝脏毒性是由氧化代谢产生的N-乙酰-对苯二酚亚胺(NAPQI)引起的。这里提出的是新的1，2-氮硼化合物，其中芳烃的CC键对被设计用于消除有毒代谢物的形成的等位元硼-氮单元取代。这项建议寻求：1)合成新的1，2-氮硼基对乙酰氨基酚的衍生物，2)通过适当的体外试验确定它们的细胞毒性和药代动力学，3)鉴定将在第二阶段STTR应用中研究的化合物。 公共卫生意义：据预测，新型阿扎波林衍生物可消除醋氨酚对肝脏的毒性。过量服用对乙酰氨基酚(更广为人知的品牌名称是泰诺(R))在美国每年导致5.6万次急诊室就诊和超过450例死亡。对乙酰氨基酚对肝脏的毒性是由代谢副产物引起的。这里提出的是新的含硼氮的对乙酰氨基酚类似物，旨在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.