With the biochemistry magic available to the liver, it’s a wonder that anything we consume is well-tolerated. Even carboxylic acids are structural alerts as they can be converted to bioreactive acyl glucoronides. The best we can do as drug hunters is minimize the risk of toxic metabolite formation and apply assays appropriately to select compounds most suited to the disease being treated. Here’s a list of the most commonly encountered bioactivatable functional groups and their corresponding reactive metabolites.
For more details on structural alerts, reactive metabolites, and de-risking strategies I recommend the following articles by Amit Kalgutkar, Antonia Stepan, and colleagues:
“Minimising the potential for metabolic activation in drug discovery.” Exp. Opin. Drug Met. & Toxicol. 2005, doi: 10.1517/17425255.1.1.91
“A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups.” Curr. Drug Metabol. 2005, 6, 161-225.
“Structural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States.” Chem. Res. Toxicol. 2011, 24, 1345-1410.
“Predicting Toxicities of Reactive Metabolite-Positive Drug Candidates.” Annu. Rev. Pharmacol. Toxicol. 2015, 55, 35-54.
“Should the Incorporation of Structural Alerts be Restricted in Drug Design? An Analysis of Structure-Toxicity Trends with Aniline-Based Drugs.” Curr. Med. Chem. 2015, 22, 438-464.
Hope this helps. Happy hunting! Explore drughunter.com for more.