Discovery of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors.
We report the synthesis and biological evaluation of aminopyridines substituted with benzoxazole. The SAR of the aminopyridines was explored to improve the inhibitory activity against c-Met and to decrease hERG affinity. These studies led to the discovery of amide 24 which showed good c-Met inhibitory potency, low affinity to hERG and favorable pharmacokinetic properties in rats.
Cho
Sung Yun
SY
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea.
Han
Sun-Young
SY
Ha
Jae Du
JD
Ryu
Jae Wook
JW
Lee
Chong Ock
CO
Jung
Heejung
H
Kang
Nam Sook
NS
Kim
Hyoung Rae
HR
Koh
Jong Sung
JS
Lee
Jongkook
J
D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry*; D055808:Drug Discovery; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D001583:Benzoxazoles; D047428:Protein Kinase Inhibitors; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases