The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors.

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Kim MH, Tsuhako AL, Co EW, Aftab DT, Bentzien F, Chen J, Cheng W, Engst S, Goon L, Klein RR, Le DT, Mac M, Parks JJ, Qian F, Rodriquez M, Stout TJ, Till JH, Won KA, Wu X, Yakes FM, Yu P, Zhang W, Zhao Y, Lamb P, Nuss JM, Xu W

The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors.

Bioorg Med Chem Lett. 2012 Aug 1;22(15):4979-85. doi: 10.1016/j.bmcl.2012.06.029. Epub 2012 Jun 16.

PubMed ID

22765894 [ View in PubMed

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Abstract

Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sunitinib	Vascular endothelial growth factor receptor 1	IC 50 (nM)	1	N/A	N/A	Details
Sunitinib	Vascular endothelial growth factor receptor 2	IC 50 (nM)	37	N/A	N/A	Details