Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.
Boezio
Alessandro A
AA
Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA; Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. aboezio@amgen.com
Berry
Loren
L
Albrecht
Brian K
BK
Bauer
David
D
Bellon
Steven F
SF
Bode
Christiane
C
Chen
April
A
Choquette
Deborah
D
Dussault
Isabelle
I
Fang
Mei
M
Hirai
Satoko
S
Kaplan-Lefko
Paula
P
Larrow
Jay F
JF
Lin
Min-Hwa Jasmine
MH
Lohman
Julia
J
Potashman
Michele H
MH
Qu
Yusheng
Y
Rex
Karen
K
Santostefano
Michael
M
Shah
Kavita
K
Shimanovich
Roman
R
Springer
Stephanie K
SK
Teffera
Yohannes
Y
Yang
Yajing
Y
Zhang
Yihong
Y
Harmange
Jean-Christophe
JC
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met