Discovery of the Novel Potent and Selective FLT3 Inhibitor 1-{5-[7-(3- Morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and Its Anti-Acute Myeloid Leukemia (AML) Activities in Vitro and in Vivo | doi.page

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Discovery of the Novel Potent and Selective FLT3 Inhibitor 1-{5-[7-(3- Morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and Its Anti-Acute Myeloid Leukemia (AML) Activities in Vitro and in Vivo

Journal of Medicinal Chemistry2012Vol. 55(8), pp. 3852–3866

Citations Over TimeTop 12% of 2012 papers

Weiwei Li, Xiaoyan Wang, Renlin Zheng, Hengxiu Yan, Zhixing Cao, Lei Zhong, Zerong Wang, Pan Ji, Lingling Yang, Lijiao Wang, Yong Xu, Jingjing Liu, Jiao Yang, Chunhui Zhang, Shuang Ma, Shan Feng, Qizheng Sun, Yuquan Wei, Shengyong Yang

Abstract

Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.

Citations Over TimeTop 12% of 2012 papers

Abstract

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