Synthesis, Structure–Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole‐3‐Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors
Synthesis, Structure–Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole‐3‐Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors
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DOI：
10.1111/j.1747-0285.2012.01365.x
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发表时间：
2012-06
影响因子：
3
通讯作者：
Deyan Wu;Fangfang Jin;Weiqiang Lu;Jin Zhu;Cui Li;Wen Wang;Yun Tang;Hualiang Jiang;Jin Huang;Guixia Liu;Jian Li
中科院分区：
文献类型：
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作者：
Deyan Wu;Fangfang Jin;Weiqiang Lu;Jin Zhu;Cui Li;Wen Wang;Yun Tang;Hualiang Jiang;Jin Huang;Guixia Liu;Jian Li
2 型糖尿病 (T2DM) 是一种代谢性疾病，也是对世界各地医疗保健系统的重大挑战。二肽基肽酶 IV (DPP-4) 是一种丝氨酸蛋白酶，已迅速成为治疗 T2DM 的有效治疗靶点。在这项研究中，通过基于结构的虚拟筛选、化学合成和生物测定的综合方法，发现了一系列以吡唑-3-碳腙支架为特征的新型DPP-4抑制剂。 SPECS 数据库的虚拟筛选，然后进行酶活性测定，产生了具有不同支架的五种微摩尔或低至中微摩尔抑制水平的化合物 (1-5)。考虑到抑制活性、结构变异性和合成可及性，选择化合物 1 进行进一步的结构修饰。合成了十七种新化合物并通过生物测定进行了测试。发现九种化合物（6e、6g、6k-l 和 7a-e）对 DPP-4 具有抑制作用。分子对接模型给出了结构-活性关系的合理解释。基于八种DPP-4抑制剂（1-5、6e、6k和7d），获得了最佳药效团模型hypo1，由1个氢键供体（HBD）、1个氢键受体（HBA）和2个疏水（HY）特征组成。对接模型和药效团作图结果均与药理学结果一致。目前的研究为进一步结构优化提供了一些指导信息，有助于未来DPP-4抑制剂的设计。
Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP‐4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP‐4 inhibitors, featuring the pyrazole‐3‐carbohydrazone scaffold, have been discovered using an integrated approach of structure‐based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low‐to‐mid‐micromolar inhibitory level compounds (1–5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k–l, and 7a–e) were found to show inhibitory effects against DPP‐4. Molecular docking models give rational explanation about structure–activity relationships. Based on eight DPP‐4 inhibitors (1–5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP‐4 inhibitors design.