Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors

被引:30
作者
Locuson, CW
Suzuki, H
Rettie, AE
Jones, JP
机构
[1] Washington State Univ, Dept Chem, Pullman, WA 99164 USA
[2] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA
[3] Meiji Seika Kaisha Ltd, Pharmaceut Res Ctr, Kohoku Ku, Yokohama, Kanagawa 2228567, Japan
[4] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA
关键词
D O I
10.1021/jm049605m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Human cytochrome P450 (CYP) 2C19 is one of the most important CYP2C family members responsible for metabolizing commonly prescribed drugs. This research describes synthetic modifications to benzbromarone (Bzbr) to create the most potent CYP2C19 inhibitor ever reported. The most important features enabling analogues of Bzbr to bind to CYP2C19 with high affinity are low acidity (high pK(a) or nonionizability) and hydrophobic substituents adjacent to the phenol moiety. Though CYP2C19 was known to prefer neutral substrates, the extent was perhaps not realized until the anionic, parent compound Bzbr (K-i = 3.7 muM) was compared to a less acidic dimethyl analogue (K-i = 0.033 muM). However, differences in affinity for anionic and neutral Bzbr analogues did not appear to affect the regiospecificity of their metabolism by CYP's 2C19 and 2C9. In addition, some Bzbr analogues were metabolized both on the phenol and benzofuran rings. By using a substrate with a methyl ether in place of the Bzbr phenol, it was shown that some Bzbr analogues must be able to freely reposition after binding and oxidize the more energetically favorable position. Normally, O-demethylation of this methyl ether is favored over benzofuran hydroxylation based on ion current from LC/MS. Deuterium substitution of the methyl ether results in an inverse isotope effect on benzofuran hydroxylation (i.e. increased oxidation of this less favorable site). Likewise, Bzbr-based CoMFA models of CYP2C19 demonstrated no clear preference for any one ligand alignment. This suggests results from this modeling method must be interpreted carefully for each CYP isoform. In summary, Bzbr analogues have demonstrated they can be adapted to other CYP2C enzymes in order to probe isoform-specific properties.
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收藏
页码:6768 / 6776
页数:9
相关论文
共 32 条
[1]  
Äbelö A, 2000, DRUG METAB DISPOS, V28, P966
[2]   Clinical significance of the cytochrome P4502C19 genetic polymorphism [J].
Desta, Z ;
Zhao, XJ ;
Shin, JG ;
Flockhart, DA .
CLINICAL PHARMACOKINETICS, 2002, 41 (12) :913-958
[3]   METABOLISM OF BENZBROMARONE IN MAN - STRUCTURES OF NEW OXIDATIVE METABOLITES, 6-HYDROXY-BENZBROMARONE AND 1'-OXO-BENZBROMARONE, AND THE ENANTIOSELECTIVE FORMATION AND ELIMINATION OF 1'-HYDROXYBENZBROMARONE [J].
DEVRIES, JX ;
WALTERSACK, I ;
VOSS, A ;
FORSTER, W ;
PONS, PI ;
STOETZER, F ;
SPRAUL, M ;
ACKERMANN, M ;
MOYNA, G .
XENOBIOTICA, 1993, 23 (12) :1435-1450
[4]   Differential roles of Arg97, Asp293, and Arg108 in enzyme stability and substrate specificity of CYP2C9 [J].
Dickmann, LJ ;
Locuson, CW ;
Jones, JP ;
Rettie, AE .
MOLECULAR PHARMACOLOGY, 2004, 65 (04) :842-850
[5]   EVIDENCE THAT CYP2C19 IS THE MAJOR (S)-MEPHENYTOIN 4'-HYDROXYLASE IN HUMANS [J].
GOLDSTEIN, JA ;
FALETTO, MB ;
ROMKESSPARKS, M ;
SULLIVAN, T ;
KITAREEWAN, S ;
RAUCY, JL ;
LASKER, JM ;
GHANAYEM, BI .
BIOCHEMISTRY, 1994, 33 (07) :1743-1752
[6]  
GOTOH O, 1992, J BIOL CHEM, V267, P83
[7]   An assessment of the reaction energetics for cytochrome P450-mediated reactions [J].
Higgins, L ;
Korzekwa, KR ;
Rao, S ;
Shou, MG ;
Jones, JP .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2001, 385 (01) :220-230
[8]   Identification of residues 99, 220, and 221 of human cytochrome P450 2C19 as key determinants of omeprazole hydroxylase activity [J].
Ibeanu, GC ;
Ghanayem, BI ;
Linko, P ;
Li, LP ;
Pedersen, LG ;
Goldstein, JA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) :12496-12501
[9]   Intramolecular isotope effects for benzylic hydroxylation of isomeric xylenes and 4,4'-dimethylbiphenyl by cytochrome P450: Relationship between distance of methyl groups and masking of the intrinsic isotope effect [J].
Iyer, KR ;
Jones, JP ;
Darbyshire, JF ;
Trager, WF .
BIOCHEMISTRY, 1997, 36 (23) :7136-7143
[10]   ISOTOPICALLY SENSITIVE BRANCHING AND ITS EFFECT ON THE OBSERVED INTRAMOLECULAR ISOTOPE EFFECTS IN CYTOCHROME-P-450 CATALYZED-REACTIONS -A NEW METHOD FOR THE ESTIMATION OF INTRINSIC ISOTOPE EFFECTS [J].
JONES, JP ;
KORZEKWA, KR ;
RETTIE, AE ;
TRAGER, WF .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1986, 108 (22) :7074-7078