Autotaxin (ATX) is the dominant catalytic enzyme accounting for the lipid mediator lysophosphatidic acid (LPA) through hydrolysis of lysophosphatidylcholine (LPC). There is great interest in developing nonacidic ATX inhibitors with a specific binding mode to serve as potential in vivo effective therapeutic tools. Herein, dating from a high-throughput screening (HTS) product Indole-1 (740 nM), a dedicated optimization campaign was implemented through derivatizing the −COOH group to versatile linkers that well-bridged the indole skeleton and the hydrophobic pocket binding groups. Ultimately, it was established that the coexistence of a carbamate linker and −OH-group-containing amines could generally furnish excellent indole-based ATX inhibitors with even below 1 nM in vitro activities. Two optimal entities were advanced to a bleomycin-induced mice pulmonary fibrosis model, which exerted promising efficacy in alleviating the damaged lung texture caused by bleomycin exposure. The novel carbamate-containing indole-based ATX inhibitors with a concrete binding mode may contribute to the identification of potential therapeutic agents to intervene in fibrotic diseases.

中文翻译：

---

新型的基于吲哚的变构高能ATX抑制剂在小鼠肺纤维化模型中具有很高的体内功效。

自分泌运动素（ATX）是占主导地位的催化酶，其通过溶血磷脂酰胆碱（LPC）的水解作用介导了脂质介导的溶血磷脂酸（LPA）。开发具有特定结合模式的非酸性ATX抑制剂作为潜在的体内有效治疗工具引起了极大的兴趣。本文中，从高通量筛选（HTS）产品Indole-1（740 nM）开始，通过将-COOH基团衍生为能很好地桥接吲哚骨架和疏水性口袋结合基团的通用接头，实施了专门的优化计划。最终，已确定氨基甲酸酯连接基和含-OH-基团的胺的共存通常可提供出色的基于吲哚的ATX抑制剂，其体外浓度甚至低于1 nM活动。两个最佳实体被推进到博来霉素诱导的小鼠肺纤维化模型中，该模型在减轻由博来霉素暴露引起的受损肺纹理方面发挥了有希望的功效。具有特定结合模式的新型的含氨基甲酸酯的吲哚基ATX抑制剂可能有助于鉴定干预纤维化疾病的潜在治疗剂。