摘要/Abstract

以Ⅱ型黏着斑激酶（FAK）抑制剂化合物2为先导化合物，结合FAK变构疏水腔的结构特征，对其尾部结构N-苯基吡唑进行了结构改造和优化，共获得9个目标化合物，其中4个化合物保持了与先导化合物同水平的酶抑制活性，N¹-（4-（6-氨基-9H-嘌呤-9-基）苯基）-N³-（1-（4-乙酰氨基苯基）-3-叔丁基-1H-吡唑-5-基）脲（9e）表现出优于先导化合物2倍的FAK抑制活性，IC₅₀值为41 nmol/L.表明N-苯基吡唑结构中苯环对位有更多结构优化空间，可通过与周边残基形成氢键从而提高化合物活性.
关键词: 黏着斑激酶, 变构疏水口袋, II型抑制剂, N-苯基吡唑, 结构优化
The structure modification and optimization focused on the N-phenylpyrazole motif of the lead compound 2 were conducted on basis of the structural features of focal adhesion kinase (FAK) allosteric hydrophobic pockets. Nine aimed compounds were designed and synthesized, among which four compounds maintained the inhibitory activity against FAK at the same level as 2. Especially, N-(4-(5-(3-(4-(6-amino-9H-purin-9-yl) phenyl) ureido)-3-(tert-butyl)-1H-pyrazol-1-yl) phenyl) ace-tamide (9e) demonstrated 2-fold higher inhibition potency than that of the lead compound with the IC₅₀ value of 41 nmol/L. It is suggested that the bioactivity could be further improved by introducing more proper groups at the 4-position of phenyl to increase the interactions between the substituents and the residues around them.
Key words: focal adhesion kinase, allosteric hydrophobic pocket, type II inhibitor, N-phenylpyrazole, structure optimization


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