| acetaminophen

Reducing Toxicity in a Commonly Used Medication

Pain Relief Minus Hepatic/Renal Side Effects

From the European Journal of Medicinal Chemistry


• We describe a novel class of diethylaminocarbonyl-2-benzenesulfamide analogs to acetaminophen/paracetamol.

• Compounds, 3b and 3r, lack the hepatotoxicity present in acetaminophen/paracetamol.

• 3b and 3r maintain analgesia and antipyresis in in vivo models.

Abstract: Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity. 1 is a non-hepatotoxic, metabolically unstable lipophilic ApAP analog that is not antipyretic. The newly synthesized 3 is a non-hepatotoxic ApAP analog that is stable, lipophilic, and retains analgesia and antipyresis. Intraperitoneal or po administration of the new chemical entities (NCEs), 3b and 3r, in concentrations equal to a toxic dose of ApAP did not result in the formation of NAPQI. Unlike livers from NCE-treated mice, the livers from ApAP-treated mice demonstrated large amounts of nitrotyrosine, a marker of mitochondrial free radical formation, and loss of hepatic tight junction integrity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these NCEs represent a novel, non-narcotic therapeutic pipeline.

Introduction: Management of acute and chronic pain is one of the most prevalent and costly public health issues worldwide. In the U.S. alone, pain affects more adults than diabetes and cancer combined with an estimated cost of $635 billion to the healthcare system each year. Current analgesics have the potential risk for abuse (e.g., opioids), liver damage (acetaminophen; ApAP), or kidney injury (non-steroidal anti-inflammatory drugs; NSAIDs). A widespread dependence on opioids, particularly following work-related accidents, and high rates of overdose in the U.S. further underscore the need for safer, effective, non-opioid pain medications. In addition to NSAIDs, N-Acetyl-4-aminophenol (acetaminophen, paracetamol, ApAP) is the most frequently used over-the-counter (OTC) analgesic and antipyretic drug. Interestingly, the utility of ApAP and NSAIDs over opioids for moderate/severe pain was demonstrated recently in a trial of 416 randomized patients with moderate/severe acute extremity pain; no difference in pain reduction was found at 2 h following a single-dose NSAID and ApAP compared to an opioid/ApAP analgesic combination.

Although ApAP has been used for several decades, its precise mechanism of action (MOA) remains unidentified. However, increasing evidence indicates that...


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