title: 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.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Donna
authors.initials: D
authors.lastname: Wei
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.forename: Ligang
authors.initials: L
authors.lastname: Qian
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamath
authors.forename: Steven
authors.initials: S
authors.lastname: Mortillo
authors.forename: Barri
authors.initials: B
authors.lastname: Wautlet
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Henley
authors.forename: Robert
authors.initials: R
authors.lastname: Jeyaseelan
authors.forename: John
authors.initials: J
authors.lastname: Tokarski
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
mesh_terms: 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
chemical_list: 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