Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase

  • J Med Chem. 2003 Mar 27;46(7):1116-9. doi: 10.1021/jm0204183.
Li Sun  1 ,  Chris Liang ,  Sheri Shirazian ,  Yong Zhou ,  Todd Miller ,  Jean Cui ,  Juri Y Fukuda ,  Ji-Yu Chu ,  Asaad Nematalla ,  Xueyan Wang ,  Hui Chen ,  Anand Sistla ,  Tony C Luu ,  Flora Tang ,  James Wei ,  Cho Tang
Affiliations
  • 1. SUGEN, Inc., 230 E. Grand Avenue, South San Francisco, California 94080, USA. [email protected]
PMID: 12646019 DOI: 10.1021/jm0204183
Abstract

To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.

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