Impact of deuteration of a pyrimidine aldehyde oxidase substrate on metabolite formation.

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. The absence or minimal AO activity in preclinical species coupled with the significant underprediction of human in-vivo clearance using in-vitro systems mean AO substrates present a significant risk of sub-optimal exposure in the clinic and potential drug failure.

A range of deuterated analogues of a pyrimidine AO substrate have been synthesised to assess the potential for reduction/elimination of AO metabolism. Together with the parent compound these analogues were incubated in human liver cytosol (HLC) +- AO specific inhibitor (Raloxifene) and rate and extent of AO metabolite formation assessed.