Synthesis, SAR, and Evaluation of 4-[2,4-Difluoro-5-(cyclopropylcarbamoyl)phenylamino]pyrrolo[2,1-f][1,2,4]triazine-based VEGFR-2 kinase inhibitors.
Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was observed with compound 37 against L2987 human lung carcinoma xenografts in athymic mice.
Cai
Zhen-Wei
ZW
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
Wei
Donna
D
Borzilleri
Robert M
RM
Qian
Ligang
L
Kamath
Amrita
A
Mortillo
Steven
S
Wautlet
Barri
B
Henley
Benjamin J
BJ
Jeyaseelan
Robert
R
Tokarski
John
J
Hunt
John T
JT
Bhide
Rajeev S
RS
Fargnoli
Joseph
J
Lombardo
Louis J
LJ
D000818:Animals; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D003521:Cyclopropanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; D040301:Vascular Endothelial Growth Factor Receptor-2