Ahlström Marie M, Ridderström Marianne, Zamora Ismael, Luthman Kristina
Discovery DMPK and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, S-431 81 Mölndal, Sweden.
J Med Chem. 2007 Sep 6;50(18):4444-52. doi: 10.1021/jm0705096. Epub 2007 Aug 14.
The cytochrome P450 (CYP) family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. CYP2C9, one of the major isoforms of the CYP family, is responsible for the phase I metabolism of a variety of drugs. The aim of the present investigation is to use rational design together with MetaSite, a metabolism site prediction program, to synthesize compounds that retain their pharmacological effects but that are metabolically more stable in the presence of CYP2C9. The model compound for the study is the nonsteroidal anti-inflammatory drug celecoxib, a COX-2 selective inhibitor and known CYP2C9 substrate. Thirteen analogs of celecoxib were designed, synthesized, and evaluated with regard to their metabolic properties and pharmacologic effects. The docking solutions and the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.
细胞色素P450（CYP）家族由一大类单加氧酶组成，这些酶介导外源性物质和内源性化合物的代谢。CYP2C9是CYP家族的主要亚型之一，负责多种药物的I相代谢。本研究的目的是结合使用合理设计和代谢位点预测程序MetaSite，来合成在存在CYP2C9的情况下保留其药理作用但代谢更稳定的化合物。该研究的模型化合物是非甾体抗炎药塞来昔布，一种COX-2选择性抑制剂且是已知的CYP2C9底物。设计、合成了13种塞来昔布类似物，并对其代谢特性和药理作用进行了评估。对接结果和MetaSite的预测提供了有用信息，从而指导设计出具有改善代谢特性的新化合物。
