1,2,3-Thiadiazole substituted pyrazolones as potent KDR/VEGFR-2 kinase inhibitors
1,2,3-Thiadiazole substituted pyrazolones as potent KDR/VEGFR-2 kinase inhibitors
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DOI：
10.1016/j.bmcl.2006.12.054
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发表时间：
2007-03-15
影响因子：
2.7
通讯作者：
Mallamo, John P.
中科院分区：
文献类型：
--
作者：
Tripathy, Rabindranath;Ghose, Arup;Mallamo, John P.
KDR激酶抑制被认为在调节血管生成中起重要作用，血管生成对肿瘤细胞的存活和增殖至关重要。最近，我们披露了一种基于结构的激酶抑制剂设计策略，该策略导致鉴定出一类新的以杂环取代吡唑酮为核心模板的VEGFR-2/KDR激酶抑制剂。大鼠S9制剂的不稳定性和大多数这些抑制剂的不良iv PK谱需要探索新的吡唑啉酮类药物，以鉴定具有改善代谢稳定性的新类似物。杂环部分的优化导致噻二唑系列吡唑酮(D)被鉴定为有效的VEGFR-2/KDR激酶抑制剂。研究了SAR修饰、激酶选择性分析和改善PK性能的结构元素。大鼠的口服生物利用度高达29%。基于Glide XP对接方法的建模结果支持了我们关于吡唑酮类药物内酰胺段与KDR激酶铰链区域相互作用的假设。(c) 2007 Elsevier Ltd.版权所有。
KDR kinase inhibition is considered to play an important role in regulating angiogenesis, which is vital for the survival and proliferation of tumor cells. Recently we disclosed a structure-based kinase inhibitor design strategy which led to the identification of a new class of VEGFR-2/KDR kinase inhibitors bearing heterocyclic substituted pyrazolones as the core template. Instability in a rat S9 preparation and poor iv PK profiles for most of these inhibitors necessitated exploration of new pyrazolones to identify new analogs with improved metabolic stability. Optimization of the heterocyclic moiety led to the identification of the thiadiazole series of pyrazolones (D) as potent VEGFR-2/KDR kinase inhibitors. SAR modifications, kinase selectivity profiling, and structural elements for improved PK properties were explored. Oral bioavailability up to 29% was achieved in the rat. Modeling results based on the Glide XP docking approach supported our postulation regarding the interaction of the lactam segment of the pyrazolones with the hinge region of the KDR kinase. (c) 2007 Elsevier Ltd. All rights reserved.