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

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

Authors :
Robert J. Schmidt
Benjamin J. Henley
Celia D’Arienzo
Jonathan Lippy
John S. Sack
Yueping Zhang
Yongmi An
John T. Hunt
Amrita Kamath
John S. Tokarski
Barri Wautlet
Veeraswamy Manne
Dianlin Xie
Punit Marathe
Donna D. Wei
Louis J. Lombardo
Kyoung S. Kim
Robert Jeyaseelan
David K. Williams
Joseph Fargnoli
Liping Zhang
Yaquan Zhang
Johnni Gullo-Brown
Zhen-Wei Cai
George L. Trainor
Robert M. Borzilleri
Source :
Journal of Medicinal Chemistry. 51:5330-5341
Publication Year :
2008
Publisher :
American Chemical Society (ACS), 2008.

Abstract

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.

Details

ISSN :
15204804 and 00222623
Volume :
51
Database :
OpenAIRE
Journal :
Journal of Medicinal Chemistry
Accession number :
edsair.doi.dedup.....f58a9baa70cfbe1d4ab37df5d6a6a243
Full Text :
https://doi.org/10.1021/jm800476q