Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors.
A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.
Cai
Zhen-Wei
ZW
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. zhenwei.cai@bms.com
Wei
Donna
D
Schroeder
Gretchen M
GM
Cornelius
Lyndon A M
LA
Kim
Kyoung
K
Chen
Xiao-Tao
XT
Schmidt
Robert J
RJ
Williams
David K
DK
Tokarski
John S
JS
An
Yongmi
Y
Sack
John S
JS
Manne
Veeraswamy
V
Kamath
Amrita
A
Zhang
Yueping
Y
Marathe
Punit
P
Hunt
John T
JT
Lombardo
Louis J
LJ
Fargnoli
Joseph
J
Borzilleri
Robert M
RM
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000473:pathology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014508:Urea; D019859:Proto-Oncogene Proteins c-met