Minimizing the DILI potential of carboxylic acid-containing drugs: a perspective

Weidolf, Lars; Wilson, Ian

doi:10.1007/s00044-023-03140-9

Cited by 2 publications

(1 citation statement)

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“…What is generally meant is a metabolite of the classes epoxide, quinoid, acyl chloride, carbenium ion or other genuinely reactive intermediate. But a metabolite such as an acyl glucuronide is often mildly reactive and might not be generally regarded as an RM; − However, in the application SpotRM we keep carboxylic acids as a SARM but with many annotations.…”

Section: Discussionmentioning

confidence: 99%

Use of Structural Alerts for Reactive Metabolites in the Application SpotRM

Claesson

2024

Chem. Res. Toxicol.

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Reactive metabolite (RM) formation is widely accepted as playing a crucial role in causing idiosyncratic adverse drug reactions (IADRs), where the liver is most affected. An important goal of drug design is to avoid selection of drug candidates giving rise to RMs and therefore risk causing problems later on involving IADRs. The simplest, initial approach is to avoid test structures that have substructures known or strongly suspected to be associated with IADRs. However, as is evident from the many case reports of IADRs, in most cases a clear association with any (bio)chemical mechanism is lacking, which makes it hard to establish any structure-toxicity relationship. Separate studies of RM formation, in vitro and in vivo, have led to likely evidence and to establishing many structural alerts (SAs) that can be used for fast selection/deselection of planned test compounds. As a background to a discussion of the concept, 25 kinase inhibitor drugs with known problems of hepatotoxicity were probed against a set of SAs contained in the application SpotRM. A clear majority of the probed drugs show liabilities as evident by being flagged by more than one of the fairly established types of SAs. At the same time, no clear SAs were found in three drugs, which is discussed in the broader context of usefulness and selection tactics of SAs in drug design.

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Section: Discussionmentioning

confidence: 99%