title: Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.
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.
authors.affiliation: Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research & Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. kyoung.kim@bms.com
authors.forename: Kyoung Soon
authors.initials: KS
authors.lastname: Kim
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Schmidt
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Donna
authors.initials: D
authors.lastname: Wei
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Dianlin
authors.initials: D
authors.lastname: Xie
authors.forename: Yaquan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Celia
authors.initials: C
authors.lastname: Darienzo
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Yueping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lippy
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: Barri
authors.initials: B
authors.lastname: Wautlet
authors.forename: Benjamin
authors.initials: B
authors.lastname: Henley
authors.forename: Johnni
authors.initials: J
authors.lastname: Gullo-Brown
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Manne
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D019859:Proto-Oncogene Proteins c-met; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D017978:Receptors, Growth Factor; C017679:2-hydroxypyridine; D010770:Phosphotransferases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2; D051941:fms-Like Tyrosine Kinase 3