Structure-Activity Relationship of Hepatotoxicity

Sci Update

Drug induced liver injury is a major cause for withdrawing a drug from development or more dramatically from the market. In a recent article, Dr. Dennis J. Pelletier et Al. performed a SAR study of hepatotoxicity. They used the data from literature and built a structure searchable database. The resulting database was analyzed to identify the chemical structures associated with liver toxicity. Data from over 1266 compounds were collected and a SAR of 38 chemical structures was developed. An interesting chemical structure highlighted as a potential liver toxin is the thiophene ring. Metabolic activation of thiophene leads to a reactive intermediate that can undergo Michael type addition with cellular nucleophiles. See figure below.

 

Interestingly, hepatotoxicity is often due to an activation of the drug resulting from Phase I metabolization. Moreover, this kind of reactive metabolite is present at low levels in the blood stream which makes them difficult to be detected.
Biomimetic technology can allow for the production of such metabolites for biological and toxicology studies which could reduce the drug development attrition due to liver toxicity.
Dennis J. Pelletier et Al.; Chem. Res. Toxicol., 2010, 23, 1215-1222

Photochemistry

Hepatochem offers a variety of photochemistry reactors and accessories that are used throughout the world to explore chemical conditions. All of our reactors are compatible with most vial formats and stirring plates. We also offer several photochemistry screening kits for calibration and accuracy.

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The Biomimetic Advantage

While microsomes have proven valuable as a predictive tool, their productive capabilities are limited. Biomimetic Chemistry, on the other hand, possesses the advantages of both chemistry and biology and is thus a much more efficient tool for metabolite synthesis.

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Metabolite Synthesis

Through our revolutionary technology, HepatoChem enables cost effective testable quantities of metabolites in-house even at the earliest stages of drug discovery. This new capability, which enables affordable early metabolite toxicity testing, offers drug companies the opportunity to save millions each year through dramatically improved drug pipelines.