Impact of deuteration of a pyrimidine aldehyde oxidase substrate on metabolite formation Paige Orwig 1 , Christina Chan 1 , Scott Martin 1* , Tom Hunt 2 , Andy Lister 2 , William McCoull 2 , Clare Gregson 2, Nicola Colclough 1 1 DMPK Oncology, AstraZeneca, Cambridge, UK, 2 Chemistry Oncology, AstraZeneca, Cambridge, UK Aldehyde oxidase (AO) is a molybdenum containing enzyme that is present predominantly in the cytosol of the liver, which catalyses the oxidations of azaheterocycles and aldehydes. AO substrates present a significant risk of sub-optimal exposure in the clinic due to minimal AO activity in the preclinical species coupled with the significant underprediction of human in-vivo clearance using in-vitro systems. To assess the potential for reduction/elimination of AO metabolism, a range of deuterated analogues have been synthesised of a pyrimidine AO substrate and were incubated with the parent compound in human liver cytosol (HLC) in the presence and absence of an AO specific inhibitor (Raloxifene). The formation of the associate AO metabolites was determined using ultra-high performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). AO metabolism occurred predominantly at the 4 position (in comparison to the 2 position) of the pyrimidine. In addition, deuterating the parent compound did not provide a significant reduction (small reduction of 2-3 fold) in AO liability and, as such, it is essential to identify AO substrates early in drug discovery to allow projects to design away from this metabolic route. References
1. Manevski, N. et al. Journal of Medicinal Chemistry. 2019;62:10955-10994 2. Zientek, M. et al. Drug Metabolism and Disposition. 2010; 38:1322-1327 3. Barr, J.T. et al. Drug Metabolism and Disposition. 2014;42:695-699
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