Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogues by cytochrome P450 3A4.
Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogues by cytochrome P450 3A4.
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DOI：
10.1021/jm201207h
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发表时间：
2012-01-12
影响因子：
7.3
通讯作者：
Jones, Jeffrey P.
中科院分区：
文献类型：
--
作者：
Dahal, Upendra P.;Joswig-Jones, Carolyn;Jones, Jeffrey P.
Compounds that coordinate to the heme-iron of cytochrome P450 (CYP) enzymes are assumed to increase metabolic stability. However, recently we observed that the type II binding quinoline carboxamide (QCA) compounds were metabolically less stable. To test if the higher intrinsic clearance of type II binding compounds relative to type I binding compounds is general for other metabolic transformations, we synthesized a library of QCA compounds that could undergo N-dealkylation, O-dealkylation, benzylic hydroxylation and aromatic hydroxylation. The results demonstrated that type II binding QCA analogs were metabolically less stable (2 to 12 fold) at sub-saturating concentration compared to type I binding counterparts for all the transformations. When the rates of different metabolic transformations between type I and type II binding compounds were compared, they were found to be in the order of N-demethylation>benzylic hydroxylation> O-demethylation> aromatic hydroxylation. Finally, for the QCA analogs with aza-heteroaromatic rings, we did not detect metabolism in aza-aromatic rings (pyridine, pyrazine, pyrimidine) indicating electronegativity of the nitrogen can change regioselectivity in CYP metabolism.
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影响因子：
3.9
作者：
Jones, JP;Mysinger, M;Korzekwa, KR
通讯作者：
Korzekwa, KR
影响因子：
7.3
作者：
Peng, Chi-Chi;Cape, Jonathan L.;Jones, Jeffrey P.
通讯作者：
Jones, Jeffrey P.
影响因子：
7.3
作者：
Ahlstrom, Marie M.;Zamora, Ismael
通讯作者：
Zamora, Ismael
影响因子：
2.9
作者：
Fleishaker, JC;Herman, BD;Azie, NE
通讯作者：
Azie, NE
影响因子：
5.5
作者：
Ghaffarzadeh, Mohammad;Bolourtchian, Mohammad;Mohsenzadeh, Farshid
通讯作者：
Mohsenzadeh, Farshid