Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.
Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
Schroeder
Gretchen M
GM
Bristol-Myers Squibb Research and Development, Princeton, New Jersey, 08543-4000, USA. gretchen.schroeder@bms.com
An
Yongmi
Y
Cai
Zhen-Wei
ZW
Chen
Xiao-Tao
XT
Clark
Cheryl
C
Cornelius
Lyndon A M
LA
Dai
Jun
J
Gullo-Brown
Johnni
J
Gupta
Ashok
A
Henley
Benjamin
B
Hunt
John T
JT
Jeyaseelan
Robert
R
Kamath
Amrita
A
Kim
Kyoung
K
Lippy
Jonathan
J
Lombardo
Louis J
LJ
Manne
Veeraswamy
V
Oppenheimer
Simone
S
Sack
John S
JS
Schmidt
Robert J
RJ
Shen
Guoxiang
G
Stefanski
Kevin
K
Tokarski
John S
JS
Trainor
George L
GL
Wautlet
Barri S
BS
Wei
Donna
D
Williams
David K
DK
Zhang
Yingru
Y
Zhang
Yueping
Y
Fargnoli
Joseph
J
Borzilleri
Robert M
RM
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D000970:Antineoplastic Agents; D004095:Dihydropyridines; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D011728:Pyridones; D019859:Proto-Oncogene Proteins c-met