Novel imidazo[1,2-a]pyridine derivatives as potent ATX allosteric inhibitors: Design, synthesis and promising in vivo anti-fibrotic efficacy in mice lung model
Novel imidazo[1,2-a]pyridine derivatives as potent ATX allosteric inhibitors: Design, synthesis and promising in vivo anti-fibrotic efficacy in mice lung model
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新型咪唑并[1,2-a]吡啶衍生物作为有效的 ATX 变构抑制剂：设计、合成和在小鼠肺模型中的体内抗纤维化功效
DOI：
10.1016/j.bioorg.2021.105590
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发表时间：
2022
影响因子：
5.1
通讯作者：
Xin Zhai
中科院分区：
文献类型：
--
作者：
Hongrui Lei;Zhen Li;Tong Li;Huinan Wu;Jing Yang;Xinlian Yang;Yu Yang;Nan Jiang;Xin Zhai
为了开发新型的变构自分泌运动因子（ATX）抑制剂，利用杂化策略将PF-8380中的氨基甲酸苄酯片段组装到GLPG-1690的咪唑并[1，2-a]吡啶骨架上。GLPG-1690中的哌嗪部分被苯环取代，以增强与相邻残基的π-π相互作用。根据基于FS-3的ATX酶促分析，通过探索氨基甲酸酯芳香部分内的取代基和检查2-乙基的影响，实施进一步的结构引导优化。最终，1,3 c的1，3-苯并二氧杂环戊烯和2-羟乙基哌嗪基团被确定为一个强大的ATX抑制剂，IC 50值为2.7 nM。随后，将13 c转入活霉素诱导的小鼠肺纤维化模型。在组织病理学和免疫组化检测中，13 c可以典型地减轻纤维化组织的严重程度，并有效地减少纤维化生物标志物α-SMA的沉积。在60 mg/kg剂量下，观察到13 c的效力与GLPG-1690相当或甚至更好，对体内ATX活性具有显著抑制作用。1，3-苯并间二氧杂环戊烯（O原子）与Phe 306之间除了基本的氢键和π-π相互作用外，额外的氢键为限制13 c的结合构象提供了很好的理论依据。最后，结合自由能的计算进行，以帮助有效地识别别构ATX抑制剂。
Aiming to develop novel allosteric autotaxin (ATX) inhibitors, hybrid strategy was utilized by assembling the benzyl carbamate fragment in PF-8380 onto the imidazo[1,2-a]pyridine skeleton of GLPG-1690. The piperazine moiety in GLPG-1690 was replaced with phenyl ring to enhance the π-π interactions with adjacent residues. In the light of FS-3 based ATX enzymatic assay, further structure-guided optimizations were implemented by exploring the substituents within the carbamate aromatic moiety and examining the effect of the 2-ethyl. Eventually,13cbearing 1,3-benzodioxole and 2-hydroxyethyl piperazine group was identified as a powerful ATX inhibitor with an IC50value of 2.7 nM. Subsequently,13cwas forwarded into anin vivobleomycin-induced mice lung fibrosis model. In histopathological and immunohistochemical assays,13ccould typically alleviate the severity of fibrosis tissues and effectively reduce the deposition of fibrotic biomarker α-SMA. At a dose of 60 mg/kg,13cwas observed equivalent or even better potency than GLPG-1690 with a significant inhibition of thein vivoATX activity. Except for the fundamental H-bond and π-π interactions, an extra H-bond between the 1,3-benzodioxole (O atom) and Phe306 offered great rationale in constraining the binding conformation of13c. Finally, binding free energy calculation was conducted to assist in the efficient identification of allosteric ATX inhibitors.