Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1- f][1,2,4]triazine based VEGFR-2 kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2005-03, Vol.15 (5), p.1429-1433
• Main Authors: Borzilleri, Robert M., Cai, Zhen-wei, Ellis, Christopher, Fargnoli, Joseph, Fura, Aberra, Gerhardt, Tracy, Goyal, Bindu, Hunt, John T., Mortillo, Steven, Qian, Ligang, Tokarski, John, Vyas, Viral, Wautlet, Barri, Zheng, Xioping, Bhide, Rajeev S.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antineoplastic agents; Biological and medical sciences; Cell Survival - drug effects; Endothelium, Vascular - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Humans; Kinase receptor; Medical sciences; Mice; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Protein Binding; SAR; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR-2
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.12.079

[Display omitted] 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.