Novel pyrrolo[2,1- f][1,2,4]triazin-4-amines: Dual inhibitors of EGFR and HER2 protein tyrosine kinases

A novel series of 5-((4-aminopiperidin-1-yl)methyl)-pyrrolo[2,1- f][1,2,4]triazin-4-amines with small aniline substituents at the C4 position were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. Compound 8l exhibited promising oral efficacy in both EGFR and HER2-driven human tum...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-01, Vol.21 (2), p.781-785
Main Authors: Fink, Brian E., Norris, Derek, Mastalerz, Harold, Chen, Ping, Goyal, Bindu, Zhao, Yufen, Kim, Soong-Hoon, Vite, Gregory D., Lee, Francis Y., Zhang, Hongjian, Oppenheimer, Simone, Tokarski, John S., Wong, Tai W., Gavai, Ashvinikumar V.
Format: Article
Language:English
Subjects:
aniline
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Cell Line, Tumor
Colonic Neoplasms - drug therapy
EGFR
HER2
Humans
Kinase inhibitor
Male
Mice
Mice, Inbred BALB C
Models, Molecular
Neoplasms - drug therapy
Neoplasms - enzymology
protein-tyrosine kinases
Protein-Tyrosine Kinases - chemistry
Protein-Tyrosine Kinases - pharmacokinetics
Protein-Tyrosine Kinases - pharmacology
Protein-Tyrosine Kinases - therapeutic use
Pyrroles - chemistry
Pyrroles - pharmacokinetics
Pyrroles - pharmacology
Pyrroles - therapeutic use
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - metabolism
Receptor, ErbB-2 - antagonists & inhibitors
Receptor, ErbB-2 - metabolism
Stomach Neoplasms - drug therapy
Triazines - chemistry
Triazines - pharmacokinetics
Triazines - pharmacology
Triazines - therapeutic use
Xenograft Model Antitumor Assays
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Summary:A novel series of 5-((4-aminopiperidin-1-yl)methyl)-pyrrolo[2,1- f][1,2,4]triazin-4-amines with small aniline substituents at the C4 position were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. Compound 8l exhibited promising oral efficacy in both EGFR and HER2-driven human tumor xenograft models. A novel series of 5-((4-aminopiperidin-1-yl)methyl)-pyrrolo[2,1- f][1,2,4]triazin-4-amines with small aniline substituents at the C4 position were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. Compound 8l exhibited promising oral efficacy in both EGFR and HER2-driven human tumor xenograft models.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.11.100