title: Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.
abstract: 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.
authors.affiliation: 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
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Boezio
authors.forename: Loren
authors.initials: L
authors.lastname: Berry
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
authors.forename: Christiane
authors.initials: C
authors.lastname: Bode
authors.forename: April
authors.initials: A
authors.lastname: Chen
authors.forename: Deborah
authors.initials: D
authors.lastname: Choquette
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.forename: Mei
authors.initials: M
authors.lastname: Fang
authors.forename: Satoko
authors.initials: S
authors.lastname: Hirai
authors.forename: Paula
authors.initials: P
authors.lastname: Kaplan-Lefko
authors.forename: Jay F
authors.initials: JF
authors.lastname: Larrow
authors.forename: Min-Hwa Jasmine
authors.initials: MH
authors.lastname: Lin
authors.forename: Julia
authors.initials: J
authors.lastname: Lohman
authors.forename: Michele H
authors.initials: MH
authors.lastname: Potashman
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Qu
authors.forename: Karen
authors.initials: K
authors.lastname: Rex
authors.forename: Michael
authors.initials: M
authors.lastname: Santostefano
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
authors.forename: Roman
authors.initials: R
authors.lastname: Shimanovich
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Springer
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Yajing
authors.initials: Y
authors.lastname: Yang
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met