Halliday R C, Jones B C, Park B K, Smith D A
Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, UK.
Eur J Drug Metab Pharmacokinet. 1997 Oct-Dec;22(4):291-4. doi: 10.1007/BF03190959.
There are several models for the CYP2D6 active site with the characteristics of their substrates and inhibitors well defined. Imipramine possesses such characteristics and is both a substrate and an inhibitor of the CYP2D6 enzyme. Possible synthetic strategies to avoid interaction with the enzyme have been investigated, including: attenuation of basicity; and alteration of rigidity and length of the alkyl chain. Imipramine inhibited the 1'-hydroxylation of bufuralol (10 microM), an in vitro marker of CYP2D6 activity, in a CYP2D6 cell line (IC50 = 2.4 microM). Inhibitory potency was attenuated by the removal of the basic centre; imipramine N-oxide had no inhibitory effect on bufuralol 1'-hydroxylation. However, removal of this basic centre, as a strategy to decrease CYP2D6 interaction, may well have a detrimental effect on pharmacological efficacy. Both an increase and decrease in the N-N carbon chain length [2C,4C] caused a reduction in inhibitory potency. In addition, introduction of a carbonyl adjacent to the amino dibenzyl moiety into 2C, 3C and 4C compounds brought about a further reduction in inhibitory potency. These data demonstrate that changes to the molecule, distal to the basic centre, can attenuate the affinity of the molecule for CYP2D6 and are in keeping with the known characteristics of the enzyme.
有几种CYP2D6活性位点模型，其底物和抑制剂的特性已得到明确界定。丙咪嗪具有这些特性，既是CYP2D6酶的底物，也是其抑制剂。已经研究了避免与该酶相互作用的可能合成策略，包括：减弱碱性；改变烷基链的刚性和长度。在CYP2D6细胞系中，丙咪嗪抑制了布非洛尔（10微摩尔）的1'-羟基化反应，布非洛尔的1'-羟基化反应是CYP2D6活性的体外标志物（IC50 = 2.4微摩尔）。去除碱性中心可减弱抑制效力；丙咪嗪N-氧化物对布非洛尔1'-羟基化没有抑制作用。然而，去除这个碱性中心作为减少CYP2D6相互作用的一种策略，很可能会对药理疗效产生不利影响。N-N碳链长度增加和减少[2C，4C]都会导致抑制效力降低。此外，在2C、3C和4C化合物的氨基二苄基部分相邻位置引入羰基会进一步降低抑制效力。这些数据表明，在远离碱性中心的分子部位进行改变，可以减弱分子对CYP2D6的亲和力，这与该酶的已知特性相符。
