Aldehyde oxidase: an enzyme of emerging importance in drug discovery.

David C. Pryde,* Deepak Dalvie, Qiyue Hu, Peter Jones, R. Scott Obach, ) and Thien-Duc Tran WorldWide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, England, Pharmacokinetics, Dynamics andMetabolism, Pfizer Global Research andDevelopment, 10628 ScienceCenterDrive, La Jolla, California 92121, WorldWide Medicinal Chemistry, Pfizer Global Research and Development, 10628 Science Center Drive, La Jolla, California 92121, and ) Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340

[1]  K. Rajagopalan,et al.  The pterin molybdenum cofactors. , 1992, The Journal of biological chemistry.

[2]  S. Munk,et al.  Characterization of brimonidine metabolism with rat, rabbit, dog, monkey and human liver fractions and rabbit liver aldehyde oxidase. , 1996, Xenobiotica; the fate of foreign compounds in biological systems.

[3]  Dennis A Smith,et al.  Does human pharmacokinetic prediction add significant value to compound selection in drug discovery research? , 2009, Current opinion in drug discovery & development.

[4]  Kuresh Youdim,et al.  In Vitro-In Vivo Correlation for Intrinsic Clearance for Drugs Metabolized by Human Aldehyde Oxidase , 2010, Drug Metabolism and Disposition.

[5]  P. C. Ruenitz,et al.  Acidic metabolites of tamoxifen. Aspects of formation and fate in the female rat. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[6]  S. Muramatsu,et al.  Stereospecific oxidation of the (S)-enantiomer of RS-8359, a selective and reversible monoamine oxidase A (MAO-A) inhibitor, by aldehyde oxidase , 2005, Xenobiotica; the fate of foreign compounds in biological systems.

[7]  M. Hayashi,et al.  Species differences in oral bioavailability of methotrexate between rats and monkeys. , 2000, Biological & pharmaceutical bulletin.

[8]  Willem P. van Hoorn,et al.  Designing Compound Subsets: Comparison of Random and Rational Approaches Using Statistical Simulation , 2007, J. Chem. Inf. Model..

[9]  C. Beedham,et al.  Biotransformation of carbazeran in guinea pig: effect of hydralazine pretreatment. , 1994, Xenobiotica; the fate of foreign compounds in biological systems.

[10]  Jeffrey P. Jones,et al.  Studies on the mechanism of aldehyde oxidase and xanthine oxidase. , 2008, The Journal of organic chemistry.

[11]  J. Gorrod,et al.  The enzymology of the in–vitro oxidation of prolintane to oxoprolintane , 1993 .

[12]  H. al-Salmy,et al.  Individual Variation in Hepatic Aldehyde Oxidase Activity , 2001, IUBMB life.

[13]  M. Monshouwer,et al.  In silico and in vitro pharmacogenetics: aldehyde oxidase rapidly metabolizes a p38 kinase inhibitor , 2011, The Pharmacogenomics Journal.

[14]  F. Guengerich,et al.  Chemical mechanisms of catalysis by cytochromes P-450: a unified view , 1984 .

[15]  Y. Moriwaki,et al.  In vitro oxidation of pyrazinamide and allopurinol by rat liver aldehyde oxidase. , 1993, Biochemical Pharmacology.

[16]  M. Relling,et al.  Racial and gender differences in N‐acetyltransferase, xanthine oxidase, and CYP1A2 * activities , 1992, Clinical pharmacology and therapeutics.

[17]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[18]  L. Lindblom,et al.  The enzyme “aldehyde oxidase” is an iminium oxidase. Reaction with nicotine Δ1′(5′) iminium ion , 1979 .

[19]  Jeffrey P. Jones,et al.  Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase. , 2007, Journal of medicinal chemistry.

[20]  P. de Miranda,et al.  6-Deoxyacyclovir: a xanthine oxidase-activated prodrug of acyclovir. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Kitamura,et al.  In vitro metabolism of fenthion and fenthion sulfoxide by liver preparations of sea bream, goldfish, and rats. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[22]  J. Bertino,et al.  The identity of rabbit-liver methotrexate oxidase. , 1965, Biochimica et biophysica acta.

[23]  A. D. Rodrigues.  Comparison of levels of aldehyde oxidase with cytochrome P450 activities in human liver in vitro. , 1994, Biochemical pharmacology.

[24]  D. Kouretas,et al.  Contribution of aldehyde oxidase, xanthine oxidase, and aldehyde dehydrogenase on the oxidation of aromatic aldehydes. , 2004, Chemical research in toxicology.

[25]  M. Fratelli,et al.  Mammalian aldehyde oxidases: genetics, evolution and biochemistry , 2008, Cellular and Molecular Life Sciences.

[26]  R. Gamage,et al.  Methadone: a potent inhibitor of rat liver aldehyde oxidase. , 1994, Biochemical pharmacology.

[27]  C. Filer,et al.  Metabolic and pharmacokinetic studies following oral administration of famciclovir to the rat and dog. , 1995, Xenobiotica; the fate of foreign compounds in biological systems.

[28]  S. Kitamura,et al.  Reduction of tertiary amine N-oxides by liver preparations: function of aldehyde oxidase as a major N-oxide reductase. , 1984, Biochemical and biophysical research communications.

[29]  S. Angelino,et al.  Covalent amination of 1-alkyl- and 1-aryl-3-carbamoylpyridinium chlorides as “model” for enzymic activity of rabbit liver aldehyde oxidase , 1984 .

[30]  Y. Lee,et al.  Metabolic interaction between methotrexate and 4'-(9-acridinylamino)methanesulfon-M-anisidide in the rabbit. , 1988, Cancer research.

[31]  H. al-Salmy.  Inter-strain variability in aldehyde oxidase activity in the mouse. , 2002, Comparative biochemistry and physiology. Toxicology & pharmacology : CBP.

[32]  Desmond O'Connor,et al.  Pharmacokinetics and metabolism studies on (3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy) pyrazolo[1,5-d][1,2,4]triazine, a functionally selective GABA(A) alpha5 inverse agonist for cognitive dysfunction. , 2006, Bioorganic & medicinal chemistry letters.

[33]  D. G. Upshall,et al.  The fate of dibenz[b,f]-1,4-oxazepine (CR) in the rat. Part II. Metabolism in vitro. , 1983, Xenobiotica; the fate of foreign compounds in biological systems.

[34]  M. Brownstein,et al.  Analysis of aldehyde oxidase and xanthine dehydrogenase/oxidase as possible candidate genes for autosomal recessive familial amyotrophic lateral sclerosis , 1995, Somatic cell and molecular genetics.

[35]  T. Maduskuie,et al.  Species-Specific Metabolism of SGX523 by Aldehyde Oxidase and the Toxicological Implications , 2010, Drug Metabolism and Disposition.

[36]  W. Takasaki,et al.  Stereoselective pharmacokinetics of RS-8359, a selective and reversible MAO-A inhibitor, by species-dependent drug-metabolizing enzymes. , 2005, Chirality.

[37]  C. Beedham,et al.  Molybdenum hydroxylases as drug-metabolizing enzymes. , 1985, Drug metabolism reviews.

[38]  R. J. Price,et al.  Metabolism of zaleplon by human liver: evidence for involvement of aldehyde oxidase , 2002, Xenobiotica; the fate of foreign compounds in biological systems.

[39]  C. Prakash,et al.  CHARACTERIZATION OF A NOVEL METABOLITE INTERMEDIATE OF ZIPRASIDONE IN HEPATIC CYTOSOLIC FRACTIONS OF RAT, DOG, AND HUMAN BY ESI-MS/MS, HYDROGEN/DEUTERIUM EXCHANGE, AND CHEMICAL DERIVATIZATION , 2005, Drug Metabolism and Disposition.

[40]  M. Rashidi,et al.  In vitro study of 6-mercaptopurine oxidation catalysed by aldehyde oxidase and xanthine oxidase. , 2007, Drug metabolism and pharmacokinetics.

[41]  J. Paxton,et al.  Inter-species variation in the metabolism and inhibition of N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (DACA) by aldehyde oxidase. , 2000, Biochemical pharmacology.

[42]  P. LoRusso,et al.  Metabolic profile of XK469 (2(R)-[4-(7-chloro-2-quinoxalinyl)oxyphenoxy]-propionic acid; NSC698215) in patients and in vitro: low potential for active or toxic metabolites or for drug–drug interactions , 2005, Cancer Chemotherapy and Pharmacology.

[43]  C. Beedham,et al.  Metabolism of 2-phenylethylamine and phenylacetaldehyde by precision-cut guinea pig fresh liver slices , 2010, European Journal of Drug Metabolism and Pharmacokinetics.

[44]  Mohamed A. Al-Omar.  IN VITRO INHIBITORY EFFECT OF QUINOLINIC ACID ON ALDEHYDE OXIDASE ACTIVITY OF GUINEA PIG LIVER: A PROPOSED MECHANISM , 2005 .

[45]  R. Obach,et al.  Human Liver Aldehyde Oxidase: Inhibition by 239 Drugs , 2004, Journal of clinical pharmacology.

[46]  B. Palmer,et al.  Cytosol mediated metabolism of the experimental antitumor agent acridine carboxamide to the 9-acridone derivative. , 1991, Biochemical pharmacology.

[47]  S. Kitamura,et al.  Involvement of liver aldehyde oxidase in sulfoxide reduction. , 1982, Chemical & pharmaceutical bulletin.

[48]  S. Dastmalchi,et al.  MOLECULAR MODELLING OF HUMAN ALDEHYDE OXIDASE AND IDENTIFICATION OF THE KEY INTERACTIONS IN THE ENZYME-SUBSTRATE COMPLEX , 2005 .

[49]  M. Rashidi,et al.  Inhibitory effects of flavonoids on molybdenum hydroxylases activity , 2010, Expert opinion on drug metabolism & toxicology.

[50]  J. McCormack,et al.  Oxidation of selected pteridine derivatives by mamalian liver xanthine oxidase and aldehyde oxidase. , 1976, Journal of pharmaceutical sciences.

[51]  Y. Moriwaki,et al.  Effect of BOF-4272 on the oxidation of allopurinol and pyrazinamide in vivo. Is xanthine dehydrogenase or aldehyde oxidase more important in oxidizing both allopurinol and pyrazinamide? , 1993, Biochemical pharmacology.

[52]  Y. Moriwaki,et al.  Distribution and pathophysiologic role of molybdenum-containing enzymes. , 1997, Histology and histopathology.

[53]  S. Kitamura,et al.  Purification of aldehyde oxidase from bovine ciliary body. , 1989, Current eye research.

[54]  S. Ohmori,et al.  Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide. , 1993, Molecular pharmacology.

[55]  D. Johns.  Human liver aldehyde oxidase: differential inhibition of oxidation of charged and uncharged substrates. , 1967, The Journal of clinical investigation.

[56]  R. Hille.  Molybdenum and tungsten in biology. , 2002, Trends in biochemical sciences.

[57]  D. Rance,et al.  Oxidative metabolism of carbazeran in vitro by liver cytosol of baboon and man. , 1985, Xenobiotica; the fate of foreign compounds in biological systems.

[58]  S. Kitamura,et al.  Involvement of mammalian liver cytosols and aldehyde oxidase in reductive metabolism of zonisamide. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[59]  D. O'connor,et al.  Aldehyde oxidase and its contribution to the metabolism of a structurally novel, functionally selective GABAA α5-subtype inverse agonist , 2006, Xenobiotica; the fate of foreign compounds in biological systems.

[60]  R. L. Felsted,et al.  N1-methylnicotinamide oxidation in a number of mammals. , 1967, The Journal of biological chemistry.

[61]  P. Jeffrey,et al.  Pharmacokinetics of the novel, high-affinity and selective dopamine D3 receptor antagonist SB-277011 in rat, dog and monkey: in vitro/in vivo correlation and the role of aldehyde oxidase , 2001, Xenobiotica; the fate of foreign compounds in biological systems.

[62]  R. Bressler,et al.  The metabolism of tolbutamide in rat liver. , 1969, The Journal of pharmacology and experimental therapeutics.

[63]  M. Strolin Benedetti,et al.  Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics , 2006, Expert opinion on drug metabolism & toxicology.

[64]  S. Clarke,et al.  Role of aldehyde oxidase in the in vitro conversion of famciclovir to penciclovir in human liver. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[65]  D. G. Walters,et al.  Inhibition of zaleplon metabolism by cimetidine in the human liver: in vitro studies with subcellular fractions and precision-cut liver slices , 2002, Xenobiotica; the fate of foreign compounds in biological systems.

[66]  C. Beedham.  Molybdenum hydroxylases: biological distribution and substrate-inhibitor specificity. , 1987, Progress in medicinal chemistry.

[67]  C. Beedham,et al.  Kinetics and specificity of guinea pig liver aldehyde oxidase and bovine milk xanthine oxidase towards substituted benzaldehydes. , 2004, Acta biochimica Polonica.

[68]  M. Rashidi,et al.  Inhibitory effects of flavonoids on aldehyde oxidase activity. , 2009, Journal of enzyme inhibition and medicinal chemistry.

[69]  M. Rashidi,et al.  In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[70]  G. Müller,et al.  Second-generation kinase inhibitors , 2005, Expert opinion on therapeutic targets.

[71]  C. Beedham,et al.  Species variation in hepatic aldehyde oxidase activity , 1987, European Journal of Drug Metabolism and Pharmacokinetics.

[72]  M. Romão,et al.  Mammalian molybdo-flavoenzymes, an expanding family of proteins: structure, genetics, regulation, function and pathophysiology. , 2003, The Biochemical journal.

[73]  R. K. Robins,et al.  Studies on the mode of oxidation of pyrazolo(3,4-d)pyrimidine by aldehyde oxidase and xanthine oxidase. , 1969, Biochemical pharmacology.

[74]  J. Collins,et al.  Zebularine metabolism by aldehyde oxidase in hepatic cytosol from humans, monkeys, dogs, rats, and mice: influence of sex and inhibitors. , 2006, Bioorganic & medicinal chemistry.

[75]  M. Rashidi,et al.  Quantitative study of the structural requirements of phthalazine/quinazoline derivatives for interaction with human liver aldehyde oxidase. , 2001, Chemical & pharmaceutical bulletin.

[76]  J. Casida,et al.  Substrate specificity of rabbit aldehyde oxidase for nitroguanidine and nitromethylene neonicotinoid insecticides. , 2006, Chemical research in toxicology.

[77]  S. Kitamura,et al.  Extremely high drug-reductase activity based on aldehyde oxidase in monkey liver. , 2001, Biological & pharmaceutical bulletin.

[78]  E. Lunney,et al.  Targeting the unactivated conformations of protein kinases for small molecule drug discovery , 2008, Expert opinion on drug discovery.

[79]  S. Kitamura,et al.  Involvement of liver aldehyde oxidase in the reduction of nicotinamide N-oxide. , 1984, Biochemical and biophysical research communications.

[80]  T. Naruke,et al.  Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic, zaleplon, between monkeys and rats. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[81]  E. Pai,et al.  The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[82]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[83]  S. Kitamura,et al.  Strain differences of liver aldehyde oxidase activity in rats. , 1995, Biochemistry and molecular biology international.

[84]  S. Kitamura,et al.  Drug-metabolizing ability of molybdenum hydroxylases. , 2006, Drug metabolism and pharmacokinetics.

[85]  Y. Moriwaki,et al.  Widespread cellular distribution of aldehyde oxidase in human tissues found by immunohistochemistry staining. , 2001, Histology and histopathology.

[86]  R. Hille.  Molybdenum-containing hydroxylases. , 2005, Archives of biochemistry and biophysics.

[87]  R. Obach,et al.  Potent inhibition of human liver aldehyde oxidase by raloxifene. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[88]  Jos H Beijnen,et al.  An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons. , 2003, Toxicology and applied pharmacology.

[89]  S. Kitamura,et al.  Variation of Hepatic Methotrexate 7‐Hydroxylase Activity in Animals and Humans , 1999, IUBMB life.

[90]  G. Izaguirre,et al.  Metabolism of Retinaldehyde and Other Aldehydes in Soluble Extracts of Human Liver and Kidney* , 1999, The Journal of Biological Chemistry.

[91]  F. Bittner,et al.  Cell biology of molybdenum. , 2006, Biochimica et biophysica acta.

[92]  A. D. Rodrigues,et al.  The in vitro hepatic metabolism of ABT-418, a cholinergic channel activator, in rats, dogs, cynomolgus monkeys, and humans. , 1994, Drug metabolism and disposition: the biological fate of chemicals.

[93]  Kevan M Shokat,et al.  Features of selective kinase inhibitors. , 2005, Chemistry & biology.

[94]  J. Sahi,et al.  Aldehyde oxidase activity and inhibition in hepatocytes and cytosolic fractions from mouse, rat, monkey and human. , 2008, Drug metabolism letters.

[95]  Y. Moriwaki,et al.  Enzymes involved in purine metabolism--a review of histochemical localization and functional implications. , 1999, Histology and histopathology.

[96]  J. Stell,et al.  Hydralazine: a potent inhibitor of aldehyde oxidase activity in vitro and in vivo. , 1985, Biochemical pharmacology.

[97]  J. Casida,et al.  Identification of aldehyde oxidase as the neonicotinoid nitroreductase. , 2005, Chemical research in toxicology.

[98]  N. Gray,et al.  Rational design of inhibitors that bind to inactive kinase conformations , 2006, Nature chemical biology.

[99]  R. Cysyk,et al.  An extremely potent anilinoacridine inhibitor of aldehyde oxidase. , 1983, Biochemical and biophysical research communications.

[100]  B. Chabner,et al.  Inhibition of first‐pass metabolism in cancer chemotherapy: Interaction of 6‐mercaptopurine and allopurinol , 1983, Clinical pharmacology and therapeutics.

[101]  C. Beedham,et al.  Enzymatic oxidation of phthalazine with guinea pig liver aldehyde oxidase and liver slices: inhibition by isovanillin. , 2004, Acta biochimica Polonica.

[102]  S. Kitamura,et al.  In vivo-in vitro relationship of methotrexate 7-hydroxylation by aldehyde oxidase in four different strain rats. , 2006, Drug metabolism and pharmacokinetics.

[103]  T. Spector,et al.  5-ethynyl-2(1H)-pyrimidinone: aldehyde oxidase-activation to 5-ethynyluracil, a mechanism-based inactivator of dihydropyrimidine dehydrogenase. , 1994, Biochemical pharmacology.

[104]  Bryan M. Li,et al.  Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections. , 2009, Journal of medicinal chemistry.

[105]  R. Obach,et al.  Ziprasidone Metabolism, Aldehyde Oxidase, and Clinical Implications , 2003, Journal of clinical psychopharmacology.

[106]  S. Chaykin,et al.  Aldehyde oxidase: catalysis of the oxidation of N 1 -methylnicotinamide and pyridoxal. , 1971, Archives of biochemistry and biophysics.

[107]  T. Bland,et al.  Inhibition by SKF-525A of the aldehyde oxidase-mediated metabolism of the experimental antitumour agent acridine carboxamide. , 1993, Biochemical pharmacology.

[108]  Peter Imming,et al.  Drugs, their targets and the nature and number of drug targets , 2007, Nature Reviews Drug Discovery.

[109]  G. Steventon,et al.  Enzyme Systems that metabolise drugs and other xenobiotics , 2002 .