As medicinal chemists become adept at designing out of cytochrome P450 (CYP) metabolic space, less common and potentially less understood modes of metabolism can begin to significantly contribute to systemic clearance. One common approach taken to reduce CYP-mediated clearance is to decrease molecular lipophilicity by replacing lipophilic electron-rich aromatic rings with polar electron-deficient heteroarenes. This often leads to reduced microsomal-based intrinsic clearance, but it can open the door to aldehyde oxidase (AO) metabolism. AO is a cytosolic enzyme whose contribution to clearance is not represented in microsome-based assays. Dramatic variation in expression, structure, and catalytic activity as a function of species and species strain, serve to potentially mask an AO liability and convolute accurate human dose prediction. In several instances this has led to investigational new drugs exhibiting extensive AO metabolism in humans. In these cases the clinical trials were terminated due to unacceptable exposure or toxicity associated with the metabolite. Fortunately, semi-qualitative <i>in vitro</i> identification of AO metabolism is straightforward and substrates bearing potential metabolic sites should be assayed early-on during lead optimization. Computational methods and reaction profiling can help to predict the likelihood and site of metabolism, and thereby guide medicinal chemists to conceive AO-stable analogs.<br/>

Aldehyde oxidase metabolism in drug discovery

254th National Meeting (2017)

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