Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
Bioorg Med Chem. 2011 Aug 1;19(15):4460-72. doi: 10.1016/j.bmc.2011.06.036. Epub 2011 Jul 7.
Human neutrophil elastase (HNE) plays an important role in tumour invasion and inflammation. A series of N-benzoylindazoles was synthesized and evaluated for their ability to inhibit HNE. We found that this scaffold is appropriate for HNE inhibitors and that the benzoyl fragment at position 1 is essential for activity. The most active compounds inhibited HNE activity with IC₅₀ values in the submicromolar range. Furthermore, docking studies indicated that the geometry of an inhibitor within the binding site and energetics of Michaelis complex formation were key factors influencing the inhibitor's biological activity. Thus, N-benzoylindazole derivatives and their analogs represent novel structural templates that can be utilized for further development of efficacious HNE inhibitors.
人中性粒细胞弹性蛋白酶 (HNE) 在肿瘤侵袭和炎症中发挥重要作用。我们合成了一系列 N-苯甲酰基吲哚，并评估了它们抑制 HNE 的能力。我们发现该支架适合 HNE 抑制剂，并且 1 位的苯甲酰片段对于活性是必需的。最活跃的化合物以亚微摩尔范围内的 IC₅₀ 值抑制 HNE 活性。此外，对接研究表明抑制剂在结合部位的几何形状和 Michaelis 复合物形成的能学是影响抑制剂生物学活性的关键因素。因此，N-苯甲酰基吲哚衍生物及其类似物代表了可用于进一步开发有效 HNE 抑制剂的新型结构模板。
