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Research ArticleArticle

CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4′-Hydroxyphenyl)-amino-6,7-
dimethoxyquinazoline: Structural Basis for Inactivation by Regioselective O-Demethylation

Fatih M. Uckun, Jason Thoen, Hao Chen, Elise Sudbeck, Chen Mao, Ravi Malaviya, Xing-Ping Liu and Chun-Lin Chen
Drug Metabolism and Disposition January 2002, 30 (1) 74-85; DOI: https://doi.org/10.1124/dmd.30.1.74
Fatih M. Uckun
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Jason Thoen
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Hao Chen
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Elise Sudbeck
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Chen Mao
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Ravi Malaviya
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Xing-Ping Liu
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Chun-Lin Chen
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Abstract

Here we report the phase I metabolism of the rationally designed Janus kinase-3 (JAK) inhibitor 4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131; JANEX-1). JANEX-1 was metabolized by the cytochrome P450 enzymes CYP1A1 and CYP1A2 in a regioselective fashion to form the biologically inactive 7-O-demethylation product 4-(4′-hydroxyphenyl)-amino-6-methoxy-7-hydroxyquinazoline (JANEX-1-M). Our molecular modeling studies indicated that the CYP1A family enzymes bind and demethylate JANEX-1 at the C-7 position of the quinazoline ring since the alternative binding conformation with demethylation at the C-6 position would result in a severe steric clash with the binding site residues. The metabolism of JANEX-1 to JANEX-1-M in pooled human liver microsomes followed Michaelis-Menten kinetics withVmax and Kmvalues (mean ± S.D.) of 34.6 ± 9.8 pmol/min/mg and 107.3 ± 66.3 μM, respectively. α-Naphthoflavone and furafylline, which both inhibit CYP1A2, significantly inhibited the formation of JANEX-1-M in human liver microsomes. There was a direct correlation between CYP1A activities and the magnitude of JANEX-1-M formation in the liver microsomes from different animal species. A significantly increased metabolic rate for JANEX-1 was observed in Aroclor 1254-, β-naphthoflavone-, and 3-methylcholanthrene-induced microsomes but not in clofibrate-, dexamethasone-, isoniazid-, and phenobarbital-induced microsomes. The formation of JANEX-1-M in the presence of baculovirus-expressed CYP1A1 and 1A2 was consistent with Michaelis-Menten kinetics. The systemic clearance of JANEX-1-M was much faster than that of JANEX-1 (5525.1 ± 1926.2 ml/h/kg versus 1458.0 ± 258.6 ml/h/kg). Consequently, the area under the curve value for JANEX-1-M was much smaller than that for JANEX-1 (27.5 ± 8.0 versus 94.8 ± 18.4 μM · h; P < 0.001).

Footnotes

  • Abbreviations used are::
    TNF
    tumor necrosis factor
    PTK
    protein tyrosine kinases
    JAK3
    Janus kinase-3
    JANEX-1
    4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline
    HPLC
    high-performance liquid chromatography
    JANEX-1-M
    4-(4′-hydroxyphenyl)-amino-6-methoxy-7-hydroxyquinazoline
    P450
    cytochrome P450
    FMO
    flavin-containing monooxygenase
    ARO
    Aroclor 1254
    BNF
    β-naphthoflavone
    CFB
    clofibrate
    DEX
    dexamethasone
    ISO
    isoniazid
    3-MC
    3-methylcholanthrene
    PHEN
    phenobarbital
    DMSO
    dimethyl sulfoxide
    MS
    mass spectrometry
    PBS
    phosphate-buffered saline
    LC
    liquid chromatography
    DNP
    dinitrophenyl
    PIPES
    piperazine-N,N′-bis(2-ethanesulfonic acid)
    BSA
    bovine serum albumin
    TEA
    tetraethylammonium
    CL
    clearance
    RT
    retention time
    VDW
    van der Waals
    DDQ
    2,3-dichloro-5,6-dicyano-1,4-benzoquinone
    • Received July 9, 2001.
    • Accepted September 27, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (1)
Drug Metabolism and Disposition
Vol. 30, Issue 1
1 Jan 2002
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Research ArticleArticle

CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4′-Hydroxyphenyl)-amino-6,7-
dimethoxyquinazoline: Structural Basis for Inactivation by Regioselective O-Demethylation

Fatih M. Uckun, Jason Thoen, Hao Chen, Elise Sudbeck, Chen Mao, Ravi Malaviya, Xing-Ping Liu and Chun-Lin Chen
Drug Metabolism and Disposition January 1, 2002, 30 (1) 74-85; DOI: https://doi.org/10.1124/dmd.30.1.74

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Research ArticleArticle

CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4′-Hydroxyphenyl)-amino-6,7-
dimethoxyquinazoline: Structural Basis for Inactivation by Regioselective O-Demethylation

Fatih M. Uckun, Jason Thoen, Hao Chen, Elise Sudbeck, Chen Mao, Ravi Malaviya, Xing-Ping Liu and Chun-Lin Chen
Drug Metabolism and Disposition January 1, 2002, 30 (1) 74-85; DOI: https://doi.org/10.1124/dmd.30.1.74
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