N(4)-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d]pyrimidines as potent multiple receptor tyrosine kinase inhibitors: design, synthesis, and in vivo evaluation.

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Gangjee A, Zaware N, Raghavan S, Yang J, Thorpe JE, Ihnat MA

N(4)-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d]pyrimidines as potent multiple receptor tyrosine kinase inhibitors: design, synthesis, and in vivo evaluation.

Bioorg Med Chem. 2012 Apr 1;20(7):2444-54. doi: 10.1016/j.bmc.2012.01.029. Epub 2012 Feb 4.

PubMed ID

22370340 [ View in PubMed

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Abstract

With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRbeta and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRbeta and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Semaxanib	Vascular endothelial growth factor receptor 2	IC 50 (nM)	2430	N/A	N/A	Details