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In Vitro Metabolism Study of a Novel P38 Kinase Inhibitor: In Silico Predictions, Structure Elucidation Using MS/MS-I

In Vitro Metabolism Study of a Novel P38 Kinase Inhibitor: In Silico Predictions, Structure Elucidation Using MS/MS-I

Hanaa Ma Hashem, Marianne A Mahrouse

Future Med Chem. 2018 Jan;10(2):201-220.

PMID: 29239233

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP586379660	PH-797804		586379-66-0	Price

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