Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery

Abstract

Aldehyde oxidase (AO) catalyzes oxidations of azaheterocycles and aldehydes, amide hydrolysis, and diverse reductions. AO substrates are rare among marketed drugs, and many candidates failed due to poor pharmacokinetics, interspecies differences, and adverse effects. As most issues arise from complex and poorly understood AO biology, an effective solution is to stop or decrease AO metabolism. This perspective focuses on rational drug design approaches to modulate AO‑mediated metabolism in drug discovery. AO biological aspects are also covered, as they are complementary to chemical design and important when selecting the experimental system for risk assessment. The authors’ recommendation is an early consideration of AO-mediated metabolism supported by computational and in vitro experimental methods but not an automatic avoidance of AO structural flags, many of which are versatile and valuable building blocks. Preferably, consideration of AO‑mediated metabolism should be part of the multiparametric drug optimization process, with the goal to improve overall drug-like properties.

Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019‐nCoV Infection

“…25 Potential DDIs between these drugs and favipiravir should be carefully monitored. Several drugs, such as citalopram, 26 zaleplon, 27 famciclovir, 28 and sulindac, 29 are also metabolized by AO. In vitro study shows that favipiravir is a mechanism based inhibitor of AO in a concentration-dependent manner between 3.14 and 942 µg/mL 15 and the previous clinical study showed a mean steady-state trough concentration of 46.1 µg/ mL in the treatment of EVD.…”

Pharmacokinetics of Favipiravir in Critically Ill Patients With COVID‐19

“…9,22 Many AO substrates report poor PKs with rapid metabolism and failed drug development. [23][24][25] Therefore, the auto-inhibition of AO is speculated to be necessary to maintain significant FPV concentration.…”

Application of In Vitro Metabolism Activation in High-Throughput Screening

“…Some compounds generate genotoxicity without metabolic activation, whereas other compounds need metabolic activation to produce their genotoxic effect, such as N-nitrosodimethylamine [92]. When a compound undergoes metabolic activation, it changes the structure or electric charge of the original chemical [93,94]; given this fact, metabolites are usually more hydrophilic than the parental compounds. These metabolites are more likely to bind to DNA, leading to corrupt replication.…”