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.
Alessandro A Boezio  1 ,  Loren Berry ,  Brian K Albrecht ,  David Bauer ,  Steven F Bellon ,  Christiane Bode ,  April Chen ,  Deborah Choquette ,  Isabelle Dussault ,  Mei Fang ,  Satoko Hirai ,  Paula Kaplan-Lefko ,  Jay F Larrow ,  Min-Hwa Jasmine Lin ,  Julia Lohman ,  Michele H Potashman ,  Yusheng Qu ,  Karen Rex ,  Michael Santostefano ,  Kavita Shah ,  Roman Shimanovich ,  Stephanie K Springer ,  Yohannes Teffera ,  Yajing Yang ,  Yihong Zhang ,  Jean-Christophe Harmange
Affiliations
  • 1. Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA; Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. [email protected]
PMID: 19819693 DOI: 10.1016/j.bmcl.2009.09.096
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.

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