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Together with Dr. Jim Daniels and Dr. Rose Wilson

A Word From Our Sponsor, Hypha Discovery:

“Drug metabolism is a critical to understand in early drug discovery. Metabolism determines the clinical dosing schedule, can be responsible for an active drug species, and can create unwanted toxic metabolites. This article provides an excellent overview of common biotransformations that one may encounter.” – Dr. Julia Shanu-Wilson, Hypha Discovery

Hypha Discovery Ltd. is a specialist CRO supporting pharma companies worldwide through production of metabolites and late-stage drug derivatives. We are experts in scalable synthesis, purification and identification of metabolites and possess a wealth of experience in the purification and structure elucidation of natural products.

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.