Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors

Bioorg Med Chem Lett. 2009 Nov 15;19(22):6307-12. doi: 10.1016/j.bmcl.2009.09.096. Epub 2009 Sep 27.


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.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Apoptosis / physiology*
  • Cell Survival
  • Humans
  • Mice
  • Mice, Nude
  • Neovascularization, Physiologic / physiology*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays


  • Angiogenesis Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-met