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Title 

Structural modifications at the 6-position of thieno[2,3-d]pyrimidines and their effects on potency at FLT3 for treatment of acute myeloid leukemia

Authors 

H KimC LeeJ S YangS ChoiC H ParkJong Soon KangSoo Jin OhJi Eun YunM H KimG Han

Publisher 

Elsevier

Issue Date 

2016

Citation 

European Journal of Medicinal Chemistry, vol. 120, no. 1, pp. 74-85

Keywords 

3-d]pyrimidineAcute myeloid leukemia (AML)Fms-like tyrosine kinase 3 (FLT3)Metabolic stabilityThieno[2

Abstract 

Fms-like tyrosine kinase 3 (FLT3) is a well-known and important target for the treatment of acute myeloid leukemia (AML). A series of thieno[2,3-d]pyrimidine derivatives from a modification at the 6-position were synthesized to identify effective FLT3 inhibitors. Although compounds 1 and 2 emerged as promising FLT3 inhibitors among the synthesized compounds, both compounds exhibited poor metabolic stability in human and rat liver microsomes. Hence, further optimization was required for the discovery of FLT3 inhibitors, with a focus on improving metabolic stability. Compound 16d, which had structural modifications of the methyl group at the 5-position and the 4-(2-methylaminoethoxy) phenyl group at the 6-position, exhibited good inhibitory activity against FLT3 and showed effective antiproliferative activity against four leukemia cell lines, including MV4-11. Moreover, compound 16d displayed enhanced metabolic stability. The results of this study indicated that 16d could be a promising compound for further optimization and development as a potent FLT3 inhibitor.

ISSN 

0223-5234

Link 

http://dx.doi.org/10.1016/j.ejmech.2016.05.022

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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