Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors.
Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors.
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DOI：
10.1021/jm049605m
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发表时间：
2004-12
影响因子：
7.3
通讯作者：
C. Locuson;Hisashi Suzuki;A. Rettie;Jeffrey P. Jones
中科院分区：
文献类型：
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作者：
C. Locuson;Hisashi Suzuki;A. Rettie;Jeffrey P. Jones
人细胞色素P450(CYP)2C19是细胞色素P450家族中最重要的成员之一，负责代谢常用药物。这项研究描述了对苯溴马龙(Bzbr)的合成修饰，以创建迄今报道的最有效的CYP2C19抑制剂。Bzbr类似物能够与高亲和力的CYP2C19结合的最重要的特征是低酸度(高pK(A)或非电离性)和靠近苯酚部分的疏水取代基。虽然已知细胞色素P-2C19更喜欢中性底物，但直到将阴离子母体化合物Bzbr(K(I)=3.7microm)与酸性较弱的二甲基类似物(K(I)=0.033微米)进行比较后，才能意识到这一程度。然而，阴离子和中性Bzbr类似物的亲和力差异似乎并不影响CYP的2C19和2C9代谢的区域特异性。此外，一些Bzbr类似物在苯酚环和苯并呋喃环上都有代谢。通过用甲醚代替BzBr苯酚的底物，证明了某些Bzbr类似物在结合后必须能够自由重定位，并氧化更有利的位置。通常情况下，基于LC/MS的离子电流，该甲醚的O-脱甲基化比苯并呋喃的羟基化更受欢迎。同样，基于Bzbr的CYP2C19的CoMFA模型没有显示出明显的对任何一个配体比对的偏好。这表明，对于每一种CYP亚型，这种建模方法的结果都必须仔细解释。综上所述，BzbR类似物已经证明它们可以适应其他CYP2C酶，以探索同工型的特定性质。
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 microM) was compared to a less acidic dimethyl analogue (K(i) = 0.033 microM). 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.