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

• Published in: Bioorganic & medicinal chemistry letters 2008-02, Vol.18 (4), p.1354-1358
• Main Authors: Cai, Zhen-wei, Wei, Donna, Borzilleri, Robert M., Qian, Ligang, Kamath, Amrita, Mortillo, Steven, Wautlet, Barri, Henley, Benjamin J., Jeyaseelan, Robert, Tokarski, John, Hunt, John T., Bhide, Rajeev S., Fargnoli, Joseph, Lombardo, Louis J.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Cytochrome P-450 Enzyme Inhibitors; Endothelial Cells - cytology; Endothelial Cells - drug effects; General aspects; Humans; Kinase inhibitors; Lung Neoplasms - drug therapy; Medical sciences; Mice; Mice, Nude; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrolo[2,1- f][1,2,4]triazine; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR-2; Xenograft Model Antitumor Assays
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.01.012

A new sub-family of pyrrolotriazine analogs was identified as the potent VEGFR-2 kinase inhibitors. Antitumor efficacy was observed with compound 37 against L2987 human lung carcinoma xenografts in athymic mice. 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.