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) Act

详细信息    查看全文

• 作者：Wei-Wei Li ; Xiao-Yan Wang ; Ren-Lin Zheng ; Heng-Xiu Yan ; Zhi-Xing Cao ; Lei Zhong ; Ze-Rong Wang ; Pan Ji ; Ling-Ling Yang ; Li-Jiao Wang ; Yong Xu ; Jing-Jing Liu ; Jiao Yang ; Chun-Hui Zhang ; Shuang Ma ; Shan Feng ; Qi-Zheng Sun ; Yu-Quan Wei ; Sheng-Yong Yang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3852-3866
• 全文大小：627K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

Structure鈥揳ctivity 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.