Medicinal chemistry approaches to avoid aldehyde oxidase metabolism

doi:10.1016/j.bmcl.2012.02.069

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 8, 15 April 2012, Pages 2856-2860

https://doi.org/10.1016/j.bmcl.2012.02.069 Get rights and content

Abstract

Aldehyde oxidase (AO) is a molybdenum-containing enzyme distributed throughout the animal kingdom and capable of metabolising a wide range of aldehydes and N-heterocyclic compounds. Although metabolism by this enzyme in man is recognised to have significant clinical impact where human AO activity was not predicted by screening in preclinical species, there is very little reported literature offering real examples where drug discoverers have successfully designed away from AO oxidation. This article reports on some strategies adopted in the Pfizer TLR7 agonist programme to successfully switch off AO metabolism that was seen principally in the rat.

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Aldehyde oxidase and its role as a drug metabolizing enzyme
2019, Pharmacology and Therapeutics
Citation 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.
Aldehyde oxidase (AO) is a cytosolic enzyme that belongs to the family of structurally related molybdoflavoproteins like xanthine oxidase (XO). The enzyme is characterized by broad substrate specificity and marked species differences. It catalyzes the oxidation of aromatic and aliphatic aldehydes and various heteroaromatic rings as well as reduction of several functional groups. The references to AO and its role in metabolism date back to the 1950s, but the importance of this enzyme in the metabolism of drugs has emerged in the past fifteen years. Several reviews on the role of AO in drug metabolism have been published in the past decade indicative of the growing interest in the enzyme and its influence in drug metabolism. Here, we present a comprehensive monograph of AO as a drug metabolizing enzyme with emphasis on marketed drugs as well as other xenobiotics, as substrates and inhibitors. Although the number of drugs that are primarily metabolized by AO are few, the impact of AO on drug development has been extensive. We also discuss the effect of AO on the systemic exposure and clearance these clinical candidates. The review provides a comprehensive analysis of drug discovery compounds involving AO with the focus on developmental candidates that were reported in the past five years with regards to pharmacokinetics and toxicity. While there is only one known report of AO-mediated clinically relevant drug-drug interaction (DDI), a detailed description of inhibitors and inducers of AO known to date has been presented here and the potential risks associated with DDI. The increasing recognition of the importance of AO has led to significant progress in predicting the site of AO-mediated metabolism using computational methods. Additionally, marked species difference in expression of AO makes it is difficult to predict human clearance with high confidence. The progress made towards developing in vivo, in vitro and in silico approaches for predicting AO metabolism and estimating human clearance of compounds that are metabolized by AO have also been discussed.
Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN)
2019, Bioorganic and Medicinal Chemistry Letters
The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.
Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics
2017, Current Opinion in Chemical Biology
Citation 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].
Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes.
A Decade of Deuteration in Medicinal Chemistry
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Citation 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
The use of deuterium substitution in an effort to produce kinetic isotope effects (KIEs) that favorably alter pharmacokinetics and metabolism in drug discovery has accelerated in the last decade. While the effects of deuteration remain highly experimentally determined and are unpredictable, an increasing number of deuterated drug candidates have progressed from early patent filings to successful proof-of-concept human studies, including the first FDA-approved deuterated drug. The scope of use of KIEs in drug design has expanded, and now deuteration of drug candidates and tool compounds, including imaging ligands, has become a welcome instrument in the arsenal of medicinal chemists. It is expected that experimentation with strategic introduction of deuterium into the structures of organic compounds will continue to increase and may enable the future development of a variety of novel drugs and chemical tools. In this chapter an update on the topic of deuterium substitution in medicinal chemistry will be provided, focusing on the diversity of ways in which medicinal chemists are using deuteration in their efforts to deliver better drugs.
Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy
2015, Drug Metabolism and Pharmacokinetics
Citation 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].
Aldehyde oxidase contributes to drug metabolism and pharmacokinetics (PK), and a few clinical studies were discontinued because of aldehyde oxidase metabolism. Its AOX1, AOX3, AOX3L1, and AOX4 isoforms are expressed in mammals, and species differences in expression profiles reflect differences in drug metabolism and PK between animals and humans. Individual differences in aldehyde oxidase activity also influence drug metabolism in humans. Moreover, the reduced solubility of the aldehyde oxidase metabolites may induce drug toxicity. Because various drugs inhibit aldehyde oxidase, assessments of ensuing drug–drug interactions (DDI) are critical for drug optimization. Although drug metabolism, PK, safety, and DDI are important, drugs such as famciclovir and O6-benzylguanine that affect aldehyde oxidase activity in humans have been reported. Recently, various in vitro approaches have been developed to predict PK in humans. However, in vitro studies on aldehyde oxidase may be hampered because of its instability. In contrast, in vivo studies on chimeric mice with humanized livers have also been focused on to predict aldehyde oxidase-mediated metabolism. Additionally, the ratios of N1-methylnicotinamide to metabolites in urinary excretions may represent useful biomarkers of aldehyde oxidase activity in humans. Thus, assessing the contributions of aldehyde oxidase to drug metabolism in humans is necessary.
Large Computational Survey of Intrinsic Reactivity of Aromatic Carbon Atoms with Respect to a Model Aldehyde Oxidase
2023, Journal of Chemical Theory and Computation

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Medicinal chemistry approaches to avoid aldehyde oxidase metabolism

Abstract

Graphical abstract

MedChemCommun

Drug Metab. Rev.

J. Med. Chem.

Biochem. J.

J. Med. Chem.

Xenobiotica

Pharmacogenomics J.

J. Med. Chem.

J. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.