Discovery of Pyrrolopyridine−Pyridone Based Inhibitors of Met Kinase: Synthesis, X-ray Crystallographic Analysis, and Biological Activities

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• 作者：Kyoung Soon Kim ; Liping Zhang ; Robert Schmidt ; Zhen-Wei Cai ; Donna Wei ; David K. Williams ; Louis J. Lombardo ; George L. Trainor ; Dianlin Xie ; Yaquan Zhang ; Yongmi An ; John S. Sack ; John S. Tokarski ; C
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 11, 2008
• 年：2008
• 卷：51
• 期：17
• 页码：5330-5341
• 全文大小：312K
• 年卷期：v.51,no.17(September 11, 2008)
• ISSN：1520-4804

文摘

Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC₅₀ value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC₅₀ values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.