In vitro metabolism study of a novel P38 kinase inhibitor: in silico predictions, structure elucidation using MS/MS-I

作者：Hashem Hanaa M A; Mahrouse Marianne A

来源：Future Medicinal Chemistry, 2018, 10(2): 201-220.

DOI：10.4155/fmc-2017-0126

• drug metabolism
• PH-797804
• rat S9 fraction

Aim: Metabolism study of PH-797804, a promising newly developed drug for treatment of chronic inflammation which inhibits P38 mitogen-activated protein kinase. Materials & methods: Susceptibility of PH-797804 to metabolism was first investigated using SMARTCyp and Xenosite web servers. Molecular docking of the drug into CYP3A4 crystal structures evaluated binding interactions with active site. The predicted results were confirmed by in vitro incubation with rat S9 fraction. Metabolites of PH-797804 were identified by MS/MS. Results: A hydroxy metabolite and a cysteine/glutathione conjugate were detected. Computational prediction of reactive site of PH-797804 was conducted. Conclusion: The probable cysteine/glutathione adduct is indicative of potential drug chemical reactivity with potential to damage DNA and may provide guidance to the design of analogs with minimum toxicity.

• 出版日期2018-1