2-Pyridylimidazoles as inhibitors of xanthine oxidase

Baldwin, J. J.; Lumma, Patricia K.; Novello, F.; Ponticello, Gerald S.; Sprague, James M.; Duggan, D E

doi:10.1021/jm00219a016

Cited by 58 publications

(23 citation statements)

References 2 publications

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“…fects in vivo that merited further progression into preclinical or even clinical studies. Notable compounds within this series of potent nonpurine XO inhibitors include Y-700 (Pyranostat) synthesised by Ishibuchi and co-workers, [8] the particularly potent inhibitor Fyx-051, [9] which combines a pyridyl-triazole scaffold that resembles the one initially developed by Baldwin et al [10] with the use of a meta-cyanopyridyl fragment similar to the meta-cyanophenyl substituent seen in Y-700 and 2-[2-(2-methoxyethoxy)-ethoxy]-5-[5-(2-methyl-pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]-benzonitrile, a recently reported, related drug candidate with potent in vivo activity but only moderate pharmacokinetic profile. [11] The first and only nonpurine-type inhibitor to obtain market approval in the EU and USA in 2008 and 2009, respectively, is 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid (TEI-6720 or febuxostat, brand names: Adenuric (EU) and Uloric (USA)).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Xanthine Oxidase by Thiosemicarbazones, Hydrazones and Dithiocarbazates Derived from Hydroxy‐Substituted Benzaldehydes

et al. 2011

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Nonpurine xanthine oxidoreductase (XOR) inhibitors represent important alternatives to the purine analogue allopurinol, which is still the most widely used drug in the treatment of conditions associated with elevated uric acid levels in the blood. By condensing mono-, di- and trihydroxybenzaldehydes with aromatic thiosemicarbazides, aryl hydrazides and dithiocarbazates, three series of structurally related Schiff bases were synthesised, characterised and tested for XOR inhibitory activity. Hydroxy substitution in the para-position of the benzaldehyde component was found to confer high inhibitory activities. Acyl hydrazones were generally less potent than thiocarbonyl-containing Schiff bases. Within the thiosemicarbazone series, chloro and cyano substituents in the para-position of the thiosemicarbazide unit increased activities further, up to potencies approximately four-times higher than that of the benchmark allopurinol, as measured under the same assay conditions. In order to illustrate the potential of the Schiff bases to bind directly to the molybdenum centre in the active site of the enzyme, a representative example (H₂L) of each inhibitor series was co-ordinated to a cis-dioxomolybdenum(VI) unit, and the resulting complexes, [MoO₂(L)MeOH], were structurally characterised. Subsequent steady-state kinetic investigations, however, indicated mixed-type inhibition, similar to that observed for inhibitors known to bind within the substrate access channel of the enzyme, remote from the Mo centre. Enzyme co-crystallisation studies are thus required to determine the exact binding mode. Finally, the coordination of representative inhibitors to copper(II) gave rise to significantly decreased IC₅₀ values, revealing an additive effect that merits further investigation.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Xanthine Oxidase by Thiosemicarbazones, Hydrazones and Dithiocarbazates Derived from Hydroxy‐Substituted Benzaldehydes

et al. 2011

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“…Pyrazole derivatives have attracted continued interest over the years due to use of this ring system as an important core structure in many drug substances, having a wide range of pharmacological applications [1][2][3][4][5][6]. Furthermore, the use of the pyrazolopyridine nucleus has pronounced pharmacological applications in anxiolytic [7], antiviral [8,9], antileishmanial [10] and anti-inflammatory agents [11].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antioxidant Evaluation of Some New Pyrazolopyridine Derivatives

Gouda

2011

Archiv der Pharmazie

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4,6-Dimethyl-1H-pyrazolo[3,4-b]pyridine-3-amine (1) was used as a key intermediate for the synthesis of imidazolopyrazole derivatives 7-11 upon interaction with 3-(2-bromoacetyl)-2H-chromen-2-one (2), 2-(benzothiazol-2-yl)-4-chloro-3-oxobutanenitrile (3), 2,3-dibromonaphthalene-1,4-dione (4), naphtha[2,3-b]oxirene-2,7-dione (5), 2,5-dichloro-3,6-dihydroxyhexa-2,5-diene-1,4-dione (6), respectively. Acetylation of 11 afforded the bis-acetyl 12. Also, the imidazolopyrimidine 15 was prepared via treatment of 1 with sodium 3,4-dioxo-3,4-dihydronaphthalene-1-sulfonate (13) in DMF followed by cyclization of the bis-pyrazolopyrimidine 14 with glacial acetic acid. On the other hand, compound 1 was reacted with (E)-1-(4-methoxyphenyl)-5-(piperidin-1-yl)pent-1-en-3-one hydrochloride (16), 2-hydroxy-3-((piperidin-1-yl)-methyl)-naphthalene-1,4-dione (17), 2-styryl-2H-indene-1,3-dione (18), enaminone 22, chloroquinoline-3-carbaldehyde 27a, chloroquinoline-(6-methyl)-3-carbaldehyde 27b and 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (28) to afford pyrazolo[3,4-a]pyrimidines 19-21, 23, 29a, 29b and 30, respectively. Also, the pyrazolopyrimidinone 33 was obtained via treatment of 1 with 1-cyanoacetyl-3,5-dimethylpyrazole (31) followed by cyclization of the formed intermediate 32 with glacial acetic acid. Finally, treatment of 1 with o-terephthalaldehyde in glacial acetic acid afforded diazepine 34. The newly synthesized compounds were screened for their antioxidant properties in which some of them exhibited promising activities. Compounds 1, 14, 15, 23, 26, 29a, 30 and 32 have the ability to protect DNA from the damage induced by bleomycin.

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“…8 An antimycobacterial 9 as well as an anthelmintic 10 activity of pyridines substituted with 1,2,4-oxadiazoles as isosteres of nicotinic acid was described. 3-(Imidazol-2-yl)pyridines are known as inhibitors of xanthine oxidase, 11 nonsteroidal antiinflammatory agents, 12 potent and selective NPY5 receptor antagonists 13 as well as being tested as KDR kinase inhibitors. 14 3-(Thiazol-2-yl)pyridines are known as inhibitors of superoxide production by human neutrophils, 15 In view of above, it would be interesting to create a combinatorial library consisting of sterically hindered 3-(azolyl)pyridines 2-6 as derivatives of nicotinic acid ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of sterically hindered 3-(azolyl)pyridines

Lukyanov¹,

Bliznets²,

Shorshnev³

2008

Arkivoc

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Sterically hindered 2,4-disubstituted 3-(1,2,4-oxadiazol-3-yl)-, 3-(imidazol-2-yl)-and 3-(thiazol-2-yl)pyridines were synthesized from the corresponding nicotinonitriles via amidoximes, amidines and thioamides, respectively. N-Alkyl-and N-arylamidines were prepared directly from nicotinonitriles using microwave technology. The series of 3-(azolyl)pyridines form a combinatorial library of heterocyclic derivatives of nicotinic acid and were examined by prognostic software PASS.

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2-Pyridylimidazoles as inhibitors of xanthine oxidase

Cited by 58 publications

References 2 publications

Inhibition of Xanthine Oxidase by Thiosemicarbazones, Hydrazones and Dithiocarbazates Derived from Hydroxy‐Substituted Benzaldehydes

Inhibition of Xanthine Oxidase by Thiosemicarbazones, Hydrazones and Dithiocarbazates Derived from Hydroxy‐Substituted Benzaldehydes

Synthesis and Antioxidant Evaluation of Some New Pyrazolopyridine Derivatives

Synthesis of sterically hindered 3-(azolyl)pyridines

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