Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors.
A versatile synthesis of the suitably functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus is described. SAR at the C-5 and C-6 positions of the 4-(3-hydroxy-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine template led to compounds with good in vitro potency against VEGFR-2 kinase. Glucuronidation of the phenol group is mitigated by incorporation of a basic amino group on the C-6 side chain of the pyrrolotriazine nucleus.
Borzilleri
Robert M
RM
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Cai
Zhen-Wei
ZW
Ellis
Christopher
C
Fargnoli
Joseph
J
Fura
Aberra
A
Gerhardt
Tracy
T
Goyal
Bindu
B
Hunt
John T
JT
Mortillo
Steven
S
Qian
Ligang
L
Tokarski
John
J
Vyas
Viral
V
Wautlet
Barri
B
Zheng
Xioping
X
Bhide
Rajeev S
RS
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014227:Triazines; D040301:Vascular Endothelial Growth Factor Receptor-2