A potent c-Met inhibitor
AMG-208 is a highly selective c-Met inhibitor with IC50 value of 9.3 nM [1]. c-Met, the receptor tyrosine kinase, and its natural ligand, hepatocyte growth factor (HGFa), are essential for normal embryonic development and are involved in cell proliferation, migration, and invasion [2].
AMG-208 is a selective c-Met inhibitor. Pre-incubation of AMG-208 with human liver microsomes for 30 minutes inhibited CYP3A4 metabolic activity for eightfold with IC50 value of 4.1 μM in a time-dependent way [1]. In PC3 cells, AMG-208 inhibited HGF-mediated c-Met phosphorylation with IC50 value of 46 nM [2].
In male Sprague-Dawley rats, AMG-208 (0.5 mg/kg i.v.) displays a high bioavailability with Cl value of 0.37 L/h/kg, Vss value of 0.38 L/kg and T1/2 value of 1 hour [2]. Deregulation of c-Met has been involved in several human cancers and AMG-208 can inhibit c-Met activity, which would be used for cancer treatment [2].
参考文献:
[1]. Boezio AA, Berry L, Albrecht BK, et al. Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors. Bioorg Med Chem Let,. 2009, 19(22): 6307-6312.
[2]. Albrecht BK, Harmange JC, Bauer D, et al. Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase. J Med Chem, 2008, 51(10): 2879-2882.
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