【文章名】Design, Structure-Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors.
Design, Structure-Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors.
作者
Renhowe, Paul A.;Pecchi, Sabina;Shafer, Cynthia M.;Machajewski, Timothy D.;Jazan, Elisa M.;Taylor, Clarke;Antonios-McCrea, William;McBride, Christopher M.;Frazier, Kelly;Wiesmann, Marion;Lapointe, Gena R.;Feucht, Paul H.;Warne, Robert L.;Heise, Carla C.;M
[摘要]：The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncol. research over the last several years. Many potent small mol. inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compds. that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clin. efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogs as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compds. in this class, such as TKI258 (I), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRb with IC50 values <0.1 mM. On the basis of its favorable in vitro and in vivo properties, compd. I was selected for clin. evaluation and is currently in phase I clin. trials.
