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.
Highlights
AbbreviationsApAP acetaminophenNAPQI N-acetyl-p-benzoquinone imineNCEs new chemical entitiesNSAIDs non-steroidal anti-inflammatory drugs acetaminophen, paracetamol, ApAP N-Acetyl-4-aminophenolOTC over-the-counterMOA mechanism of actionAM404 N-arachidonoyl-phenolamineFAAHs fatty acid amide hydrolase enzymestransient receptor potential vanilloid-1 (TRPV1) transient receptor potential vanilloid 1CYP450 cytochrome P450
As others have done recently [22], we developed a method for NAPQI and 8 detection using ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS) in the serum of mice treated with toxic doses (600 mg/kg) of ApAP and our leading compounds
We describe novel ApAP analogs that in pre-clinical in vivo models lack hepatotoxicity, yet retain analgesia and antipyresis through an efficient synthesis by the ring opening of the heterocyclic moiety in compound 1 to supply the corresponding N-substituted amides
Summary
NSAIDs non-steroidal anti-inflammatory drugs acetaminophen, paracetamol, ApAP N-Acetyl-4-aminophenol. Because of ApAP’s narrow therapeutic index and the clinical demand for safer novel non-opioid analgesics, we undertook a research effort to find ApAP analogs that lacked hepatotoxicity. To modulate the pharmacokinetic profile of 1, a new series of analgesics is described. These compounds are obtained by the ring opening of the imide moiety in 1 to yield the corresponding N-substituted amides 3 [16]. The synthesis and characterization of the novel class of analogs depicted in 3 are described to identify new chemical entities that lack hepatotoxicity and maintain analgesic and antipyretic properties. Compared to 2, the novel 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analogs exhibit increased stability, elevated lipophilicity, and slowed hydrolysis of the amide group
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