Structural and PK-guided identification of indole-based non-acidic autotaxin (ATX) inhibitors exhibiting high invivo anti-fibrosis efficacy in rodent model
Structural and PK-guided identification of indole-based non-acidic autotaxin (ATX) inhibitors exhibiting high invivo anti-fibrosis efficacy in rodent model
复制标题
基于吲哚的非酸性自分泌运动因子 (ATX) 抑制剂的结构和 PK 指导鉴定在啮齿动物模型中表现出高体内抗纤维化功效
DOI：
10.1016/j.ejmech.2021.113951
复制
发表时间：
2022
影响因子：
6.7
通讯作者：
Xin Zhai
中科院分区：
文献类型：
--
作者：
Hongrui Lei;Zhi Cao;Huinan Wu;Tong Li;Xinyu Wang;Yuxiang Chen;Enlong Ma;Lixin Sun;Xin Zhai
近几十年来，自分泌运动因子（ATX）/溶血磷脂酸（LPA）轴的药理学靶向解释了出色的疾病管理益处。在此，为了扩展结构-活性关系（SAR）的范围，制备了十五种基于吲哚的氨基甲酸酯衍生物（1-15）以评估ATX抑制效力。其中，具有吗啉部分的化合物4被鉴定为最佳ATX抑制剂（0.41 nM），上级于阳性对照GLPG 1690（2.90 nM）。为了解决药代动力学（PK）性质差的棘手问题，引入脲部分作为氨基甲酸酯的替代物，其提供化合物16 -30。专用修饰鉴定了具有令人满意的水溶性和PK特征的二乙醇胺实体30，ATX抑制的牺牲最小（2.17 nM）。在博来霉素激发的小鼠肺纤维化模型中评价最有希望的候选物30的抗纤维化作用。经30处理后，肺匀浆和支气管肺泡液（BALF）样品中的体内ATX活性均显著下调。肺组织中促纤维化细胞因子转化生长因子-β（TGF-β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的基因表达均降至正常水平。总的来说，有希望的生物学效应可能促进30在纤维化相关疾病中的潜在应用。
In recent decades, pharmacological targeting of the autotaxin (ATX)/lysophosphatidic acid (LPA) axis accounted for excellent disease management benefits. Herein, to extend the scope of structure-activity relationships (SARs), fifteen indole-based carbamate derivatives (1–15) were prepared to evaluate the ATX inhibitory potency. Among them, compound4bearing morpholine moiety was identified as the optimal ATX inhibitor (0.41 nM), superior to the positive control GLPG1690 (2.90 nM). To resolve the intractable issue of poor pharmacokinetic (PK) property, urea moiety was introduced as a surrogate of carbamate which furnished compounds16–30. The dedicated modification identified the diethanolamine entity30with satisfactory water solubility and PK profiles with a minimum sacrifice of ATX inhibition (2.17 nM). The most promising candidate30was evaluated for anti-fibrosis effect in a bleomycin challenged mice lung fibrosis model. Upon treatment with30, thein vivoATX activity in both lung homogenate and broncheoalveolar fluid (BALF) sample was significantly down-regulated. Furthermore, the gene expression of pro-fibrotic cytokines transforming growth factor-β (TGF-β), interleukin- 6 (IL-6) and tumor necrosis factor-α (TNF-α) in lung tissue was reduced to normal level. Collectively, the promising biological effects may advocate potential application of30in fibrosis relevant diseases.