國家衛生研究院 NHRI:Item 3990099045/7180
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    题名: Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3)
    作者: Lin, WH;Hsu, JTA;Hsieh, SY;Chen, CT;Song, JS;Yen, SC;Hsu, T;Lu, CT;Chen, CH;Chou, LH;Yang, YN;Chiu, CH;Chen, CP;Tseng, YJ;Yen, KJ;Yeh, CF;Chao, YS;Yeh, TK;Jiaang, WT
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Preclinical investigations and early clinical trials suggest that FLT3 inhibitors are a viable therapy for acute myeloid leukemia. However, early clinical data have been underwhelming due to incomplete inhibition of FLT3. We have developed 3-phenyl-1H-5-pyrazolylamine as an efficient template for kinase inhibitors. Structure-activity relationships led to the discovery of sulfonamide, carbamate and urea series of FLT3 inhibitors. Previous studies showed that the sulfonamide 4 and carbamate 5 series were potent and selective FLT3 inhibitors with good in vivo efficacy. Herein, we describe the urea series, which we found to be potent inhibitors of FLT3 and VEGFR2. Some inhibited growth of FLT3-mutated MOLM-13 cells more strongly than the FLT3 inhibitors sorafenib (2) and ABT-869 (3). In preliminary in vivo toxicity studies of the four most active compounds, 10f was found to be the least toxic. A further in vivo efficacy study demonstrated that 10f achieved complete tumor regression in a higher proportion of MOLM-13 xenograft mice than 4 and 5 (70% vs. 10% and 40%). These results show that compound 10f possesses improved pharmacologic and selectivity profiles and could be more effective than previously disclosed FLT3 inhibitors in the treatment of acute myeloid leukemia.
    日期: 2013-06
    關聯: Bioorganic and Medicinal Chemistry. 2013 Jun;21(11):2856-2867.
    Link to: http://dx.doi.org/10.1016/j.bmc.2013.03.083
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0968-0896&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000319002600005
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84877811521
    显示于类别:[蔣維棠] 期刊論文
    [葉燈光] 期刊論文
    [趙宇生(2002-2013)] 期刊論文
    [陳炯東] 期刊論文
    [徐祖安] 期刊論文

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