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Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2009 Nov 15; Vol. 19 (22), pp. 6307-12. Date of Electronic Publication: 2009 Sep 27. - Publication Year :
- 2009
-
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.
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 19
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 19819693
- Full Text :
- https://doi.org/10.1016/j.bmcl.2009.09.096