Potential for the Development of a Non-Hepatotoxic Acetaminophen Alternative

Scientists have recently identified a chemical analog of acetaminophen (ApAP) that appears to have decreased liver and kidney toxicity. The peer-reviewed publication, “A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis,” by Bazan et al. will be released in the European Journal of Medicinal Chemistry on September 15, 2020. The researchers represented the LSUHS School of Medicine in New Orleans, as well as the Department of Organic Chemistry at the University of Alcala in Madrid.i  Though the drug remains in the earlier stages of testing and approval, it could have immense implications as a potential acetaminophen alternative. Research has shown that an estimated 100 million Americans in the U.S. suffer from chronic pain and that the resulting healthcare expense is upwards of 560 billion USD.ii  

Referred to in the paper as “3,” 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide was produced via several steps, the first introducing a 1,1-dioxo-1,2-benzothiazol-3-one moiety onto an existing methyl group of ApAP. The resulting compound, denoted “1,” was found to have a similar analgesic profile to ApAP, but metabolized too rapidly in vivo. was then reacted with a variety of different amines, resulting in an N-substituted amide. The addition of an amine nucleophile to the carbonyl with the sulfonamide leaving group finally resulted in the production of 3, the candidate acetaminophen alternative. The chemical reactions took place in relatively cheap polar solvents, such as water or ethanol, and were carried out at room temperature until thin-layer chromatography indicated the depletion of reagent 1. A detailed visual of this reaction is available online for open access in the European Journal of Medicinal Chemistry. 

ApAP, though considered safe in most industrialized countries, is the number one cause for acute fulminant hepatic failure.iii For this reason, researchers have long sought to identify the source of this toxicity and identify a less volatile acetaminophen alternative. Bazan et. al performed in vitro hepatotoxicity assays on 3 by measuring relative LDH and GSH production, as well as in vivo assays using a dosage of 600mg/kg, with liver function tests as an indicator. Serum creatinine and cytochrome P450 enzyme metabolism assays were also performed to indicate renal function and potential drug-drug interactions, respectively. 3 outperformed ApAP in each assay in terms of cell damage, serum creatinine levels, and cytochrome isoenzyme interaction. Researchers further identified that the oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) was responsible for heightened markers of free radical formation, loss of hepatic tight junctions, and increased number of apoptotic nuclei in liver cells resulting from ApAP exposure. 

Importantly, showed overall promise as a pain-reducing medication. Two methodologically distinct analgesic assays found that compared to ApAP, 3 similarly resulted in a significant reduction of visceral and inflammatory pain. Furthermore, a Baker’s yeast-induced hyperthermia model showed that both compounds had significant fever-reducing abilities. 

The researchers at LSU have given the rights for further research and marketing of 3 to South Rampart Pharma, LLC, a Louisiana-based company which focuses on the development of opioid alternatives and non-addictive pain medications. Hernan Bazan, the founder of the startup, reports, “We currently working to finalize the preclinical data package necessary to submit our lead molecule for the first Investigation New Drug application by the third quarter of 2020, followed by the rapid initiation of Phase 1 clinical trials to evaluate safety. Ongoing preclinical studies have reproduced these extensive proof of concept studies confirming that our lead compound shows pain reduction with absent liver and kidney toxicity.”iv 


[i] Louisiana State University. Researchers discover new class of safer analgesics. Medical Xpress. Published July 6, 2020. Accessed August 7, 2020.

[ii] Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, D.C.: National Academies Press; 2011.

[iii] Brune K, Renner B, Tiegs G. Acetaminophen/paracetamol: A history of errors, failures and false decisions. European Journal of Pain. 2014;19(7):953-965. doi:10.1002/ejp.621.

[iv] BioSpace. South Rampart Pharma Identifies New Class of Non-Opioid Pain Medicines in European Journal of Medicinal Chemistry Publication. BioSpace. Published July 14, 2020. Accessed August 7, 2020.