Linked Life Data

11744615

Source:http://linkedlifedata.com/resource/pubmed/id/11744615

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2001-12-17
pubmed:abstractText
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 with V(max) and K(m) values (mean +/- S.D.) of 34.6 +/- 9.8 pmol/min/mg and 107.3 +/- 66.3 microM, respectively. alpha-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-, beta-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 microM. h; P < 0.001).
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
74-85
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:11744615-Animals, pubmed-meshheading:11744615-Capillary Permeability, pubmed-meshheading:11744615-Cell Line, pubmed-meshheading:11744615-Chromatography, High Pressure Liquid, pubmed-meshheading:11744615-Cytochrome P-450 CYP1A1, pubmed-meshheading:11744615-Cytochrome P-450 CYP1A2, pubmed-meshheading:11744615-Dogs, pubmed-meshheading:11744615-Enzyme Inhibitors, pubmed-meshheading:11744615-Female, pubmed-meshheading:11744615-Guinea Pigs, pubmed-meshheading:11744615-Humans, pubmed-meshheading:11744615-Janus Kinase 3, pubmed-meshheading:11744615-Macaca fascicularis, pubmed-meshheading:11744615-Mast Cells, pubmed-meshheading:11744615-Mice, pubmed-meshheading:11744615-Microsomes, Liver, pubmed-meshheading:11744615-Models, Molecular, pubmed-meshheading:11744615-Passive Cutaneous Anaphylaxis, pubmed-meshheading:11744615-Protein Binding, pubmed-meshheading:11744615-Protein-Tyrosine Kinases, pubmed-meshheading:11744615-Quinazolines, pubmed-meshheading:11744615-Rabbits, pubmed-meshheading:11744615-Rats, pubmed-meshheading:11744615-Rats, Sprague-Dawley, pubmed-meshheading:11744615-Recombinant Proteins, pubmed-meshheading:11744615-Species Specificity, pubmed-meshheading:11744615-Stereoisomerism
pubmed:year
2002
pubmed:articleTitle
CYP1A-mediated metabolism of the Janus kinase-3 inhibitor 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline: structural basis for inactivation by regioselective O-demethylation.
pubmed:affiliation
Department of Pharmaceutical Sciences, Parker Hughes Cancer Center, 2665 Long Lake Road, Suite 330, St. Paul, MN 55113, USA. fatih_uckun@ih.org
pubmed:publicationType
Journal Article, In Vitro