First marketed in the US in 1953, paracetamol (acetaminophen) is one of the most widely used drugs in Western society, both in over-the-counter (OTC) products and as a component of prescription medicines. Effective in relieving pain and fever, paracetamol is noted for the absence of gastro-intestinal side-effects at therapeutic doses in contrast to the non-steroidal anti-inflammatory drugs. Exceeding the recommended dose of paracetamol (typically 4000mg daily for adults), however, can cause liver damage. Adverse events range from minor changes in liver enzymes to acute liver failure and, in some cases, death.
The toxicity is not due to paracetamol itself, but a reactive metabolite, NAPQI. Normally, NAPQI is rapidly de-toxified by conjugation with glutathione, but the pathway can become saturated as a result of overdose, combination with alcohol, or in individuals with polymorphisms in the P450 metabolizing enzymes. Inadvertent overdose can occur through combination of OTC products with prescription medicines.
In recent years, analogues of paracetamol with reduced potential for hepatic toxicity, such as the saccharin derivative, SCP-1, have been described. SCP-1 is rapidly metabolized to SCP-123, which is believed to be responsible for efficacy. Development of such analogues has been hampered by the lack of a cost-effective synthesis, but Louisiana chemists have now described a viable route to SCP-123. The synthesis comprises three steps from commercially available starting materials, requires no chromatographic purification and is amenable to large-scale processing. Full details are published in Organic Process Research & Development.