Ligand-Based Design of a Potent and Selective Inhibitor of Cytochrome P450 2C19
Ligand-Based Design of a Potent and Selective Inhibitor of Cytochrome P450 2C19
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DOI：
10.1021/jm201346g
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发表时间：
2012-02-09
影响因子：
7.3
通讯作者：
Wahlstrom, Jan L.
中科院分区：
文献类型：
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作者：
Foti, Robert S.;Rock, Dan A.;Wahlstrom, Jan L.
合成了一系列基于奥美拉唑的类似物，并对其对细胞色素P450 2C19的抑制活性进行了评价。这些数据被用来建立该系列的CYP2C19抑制药效团模型。该模型被用来设计额外的类似物，这些类似物对CYP2C19具有抑制作用。在确定了CYP2C19的抑制剂后，基于配基的设计转向了减弱许多抑制剂的快速清除。虽然大多数类似物都是在其脂肪族侧链上进行代谢的，但代谢物鉴定表明，对于化合物30这样的类似物，其硫磺部分含有杂环，代谢主要发生在苯并咪唑部分。化合物30具有较好的代谢稳定性(Cl-int=12.4mL/min/nmoL)，并选择性地抑制细胞色素P-2C19催化的(S)美苯妥因在人肝微粒体中的羟化。最后，将具有代表性的化合物对接到CYP2C19的同源模型中，以了解其良好的抑制或代谢特性。
A series of omeprazole-based analogues was synthesized and assessed for inhibitory activity against CYP2C19. The data was used to build a CYP2C19 inhibition pharmacophore model for the series. The model was employed to design additional analogues with inhibitory potency against CYP2C19. Upon identifying inhibitors of CYP2C19, ligand-based design shifted to attenuating the rapid clearance observed for many of the inhibitors. While most analogues underwent metabolism on their aliphatic side chain, metabolite identification indicated that for analogues such as compound 30 which contain a heterocycle adjacent to the sulfur moiety, metabolism primarily occurred on the benzimidazole moiety. Compound 30 exhibited improved metabolic stability (Cl-int = 12.4 mL/min/nmol) and was selective in regard to inhibition of CYP2C19-catalyzed (S)-mephenytoin hydroxylation in human liver microsomes. Finally, representative compounds were docked into a homology model of CYP2C19 in an effort to understand the favorable inhibition or metabolism properties.