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Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor.
- Source :
-
European Journal of Medicinal Chemistry . Jun2016, Vol. 116, p239-251. 13p. - Publication Year :
- 2016
-
Abstract
- c-Met/HGF overexpression has been detected in many human malignancies including tumors which are resistant to anticancer therapy. Disrupting the aberrant c-Met/HGF axis has enjoyed significant progress in both preclinical and clinical antitumor campaign. To eliminate the OCH 2 -related metabolic deficiency of our previously reported triazolotriazine 2 , we synthesized a series of CH 2 -/CF 2 -linked triazolotriazines and assessed their c-Met activities, leading to the highly potent compound 23 with IC 50 values of 0.24 nM of enzymatic activity in c-Met and 0.85 nM of cellular activity in EBC-1 cancer cell line, as well as with complete tumor regression in EBC-1 xenograft mice model at dose of 25 mg/kg via oral administration. Based on its potent anti-proliferative activities and favorable pharmacokinetic properties, 23 has been selected as a drug candidate for preclinical investigation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 116
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 115266049
- Full Text :
- https://doi.org/10.1016/j.ejmech.2016.03.076