Impact of a single biotransformation leading to intramolecular reactions and chemical degradation
Through CYP-mediated oxidation of a pyrazole group
Our paper pick for June 2024 by scientists at AstraZeneca highlights how a single biotransformation event led to several unusual metabolites that were proposed to arise from intramolecular reactions and chemical degradation of a key reactive metabolite.
The lead series initially appeared to be subject to complex metabolic events, however further investigations revealed that these four unusual metabolites were likely derived from intramolecular reactions and chemical degradations following a single CYP-mediation biotransformation of the pyrazole. A reactive and short-lived epoxide intermediate was postulated to result in two possible reaction pathways involving intramolecular rearrangement and/or chemical degradation to form M1 to M4.
Evidence for involvement of a reactive intermediate was obtained from the presence of adducts in trapping experiments with 2-mecaptoethanol, although the position of the adduct could not be localised.
Notably it was difficult to elucidate the structure of M1 due to rapid degradation of the isolated material, however sufficient data was obtained to propose the rather unusual structure of this metabolite. The structure was proposed to result from loss of the side chain and cleavage of the pyrazole ring. Stability issues were also encountered with degradants M2 to M4, with both M2 and M3 eventually converted to M4 via sequential losses of 2 Da. NMR analysis of M4 revealed cyclisation of the pendent 3-amine of 3,4-diaminetetrahydropyran group to the pyrazole ring through an intramolecular reaction.
The observation that a single biotransformation event initiated the subsequent formation of all the products M1 to M4 provided a clear focus towards designing analogues not subject to this metabolic activation.
Paper
Paper: The role of intramolecular reactions and chemical degradation in the apparent biotransformation pathways of a series of SYK inhibitors. Calle B, Barlaam B, Diene C, Lenz E, Martin S, Sarkar U, Wilkinson S, Pike A. Drug Metab Dispos. 2024 Apr 29:DMD-AR-2024-001659. doi: 10.1124/dmd.124.001659