Comments on recent development regarding reactive metabolites are posted here.
On Elimination Reactions, Addendum
Highlighting a new example of the principle, a recently published JAK inhibitor, YYWS001, containing a 2,2,3,3,3,3-pentafluorobutanamine substructure can be oxidatively bioactivated to an aldehyde that eliminates HF.
30 Mar 2026
On Elimination Reactions. Part II, Conjugated Keto Compounds
Comments on formation of conjugated keto compounds initiated by amine oxidation or O-dealkylation
10 Mar 2026
This post is the second on how different groups can behave as leaving groups (LG) in elimination reactions. Here, focus is on examples of how an initial oxidation leads to formation of conjugated keto compounds. Part I was about formation of quinone methides initiated by hydroxylation on aromatics or release of a phenol by O-dealkylation…
Compounds mentioned: felbamate, TAK-994, amcenestrant, ximelagatran, atomoxetine, and more..
On Elimination Reactions. Part I Methides
Comments and hypotheses on various leaving groups involved in methide formation. Part II will be on unsaturated keto compounds.
24 Feb 2026
The most common initiating reaction on a path to a reactive metabolite (RM) is an oxidation where the P450 enzymes play a prominent role while other enzymes, for example various flavin-containing oxidases are less important. After the first insertion of an oxygen usually something more has to happen to generate a reactive metabolite (direct formation of an epoxide on a double bond is an exception). The next step can be elimination of water over one or several bonds, e.g. to form a conjugated keto compound, or…
Compounds mentioned: cenobamate, fluorofelbamate, sorbinil, safinamide, leniolisib, centicaftor, and more..
On Methides and Azafulvenes
Comments on how some alkylarenes may form reactive metabolites
7 Dec 2025
We know that reactive metabolites (RM) come in many different forms and the current knowledge base is large. Yet it is not often that we can claim sufficient knowledge to say that a chosen drug structure will not cause RM problems. Part of the problem is probably that we could use knowledge more efficiently. To honor this message, I will highlight a subclass of RMs, quinone methides (QM), which I think has been treated somewhat stepmotherly in comparison with other bioactivation routes where arenes are involved…
Compounds mentioned: meloxicam, zolmitriptan, 4-trifluoromethylphenol.
Liver Toxicity: Structural Knowledge May Help Avoiding Rare Drug Adverse Events
Comments on possible links between recent observations of hepatotoxicity and reactive metabolites
27 Sep 2025 (updated 5 Oct)
Many obstacles have to be overcome before a new drug can be launched but the challenges do not stop there. The approved drug being used in many more patients than in the clinical trials, rare adverse effects (AE) are more likely to show up. Especially problematic is idiosyncratic drug induced liver injury (iDILI), which has caused licensed drugs to be withdrawn or more often be…
Compounds mentioned: KSQ-4279, TNG-6132, I-138, pexidartinib, lapatinib, danuglipron, fezolinetant, phencyclidine.
On Structural Alerts for Reactive Metabolites in the Recent Literature
A few glimpses from the recent literature; posted on LinkedIn on 4 May 2025. PDF available here.
Having followed the scientific literature on reactive metabolites (RM) for almost twenty years, I have noticed a shift in how and what researchers publish. Formation of RMs from drugs is important because it is the main cause of idiosyncratic drug induced liver injury (iDILI), which has terminated many drugs in clinical development, latest the GLP-1 recepto…
Compounds mentioned: zolmitriptan, ibudilast, metoprolol, donepezil, TAK-994, TAK-861, JNJ-8003