Medicinal chemistry approaches to avoid aldehyde oxidase metabolism
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Aldehyde oxidase and its role as a drug metabolizing enzyme
2019, Pharmacology and TherapeuticsCitation Excerpt :showed abnormally low AO activities in two of the donors that were alcoholic (Fu et al., 2013). Recent interruptions in the clinical development of AO substrates and the lack of correlation in AO liability with the physicochemical properties (Dalvie et al., 2012; Linton et al., 2011; Pryde et al., 2010; Pryde et al., 2012) have resulted in generation of computational and chemical and in vitro approaches to discern the role of AO in its ability to metabolize new candidates. Several computational approaches have been developed in the past decade that can help to identify compounds that are susceptible to AO metabolism.
Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN)
2019, Bioorganic and Medicinal Chemistry LettersStructural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics
2017, Current Opinion in Chemical BiologyCitation Excerpt :In addition, they reduce certain amino-groups and sulfo-groups [11]. Human AOX1 is recognized to play an important role in phase-I drug metabolism and it is involved in the oxidation of several antiviral, hypnotic and antiepileptic agents [12–18]. AOX1 substrates are often intermediates or products of cytochrome-P450-dependent metabolism [13,19–21].
A Decade of Deuteration in Medicinal Chemistry
2017, Annual Reports in Medicinal ChemistryCitation Excerpt :However, other enzymatic mechanisms have also been recognized as causing rapid drug metabolism. Among these, aldehyde oxidase (AO) has gained notoriety for its ability to oxidize aromatic nitrogen heterocycles and for the difficulty scientists experience in attempting to translate in vitro AO intrinsic clearance to in vivo clearance.19,20 DIEs have been experimentally determined for a number of AO substrates and have been correlated with in vitro and in vivo pharmacokinetic parameters for deuterated versions of two clinical compounds, 1-[2H]-carbazeran (7) and 2-[2H]-zoniporide (8) (Fig. 3).21
Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy
2015, Drug Metabolism and PharmacokineticsCitation Excerpt :Dalvie et al. [99] showed that zoniporide analogs with short half-lives were modified and subsequently monitored CLogD, electrophilicity parameters, and the energetic formation of tetrahedral intermediates [99]. Pryde et al. prevented aldehyde oxidase metabolism by considering steric bulk and electron density of toll-like receptor subtype 7 agonists [100]. Linton et al. also designed novel selective androgen receptor antagonists by introducing substituents, replacing imidazopyrimidine moieties, and blocking metabolic sites of N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}imidazo(1,2-a)pyrimidine-3-carboxamide analogs [101].
Large Computational Survey of Intrinsic Reactivity of Aromatic Carbon Atoms with Respect to a Model Aldehyde Oxidase
2023, Journal of Chemical Theory and Computation