Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Med Chem. 2020 Jul 9;63(13):7326-7346. doi: 10.1021/acs.jmedchem.0c00506. Epub 2020 Jun 12.
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 effective therapeutic tools. Herein, dating from a high-throughput screening (HTS) product (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 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.
自分泌酶（Autotaxin，ATX）是通过水解溶血磷脂酰胆碱（Lysophosphatidylcholine，LPC）产生脂质介质溶血磷脂酸（Lysophosphatidic acid，LPA）的主要催化酶。开发具有特定结合模式的非酸性 ATX 抑制剂以作为潜在有效的治疗工具引起了广泛关注。本文从高通量筛选（HTS）产物（740 nM）出发，通过将 -COOH 基团衍生化为各种连接子，从而良好地桥连吲哚骨架和疏水口袋结合基团，对其进行了专门的优化。最终发现，氨基甲酸酯连接子和含有 -OH 基团的胺的共存通常可以提供具有甚至低于 1 nM 活性的极好的基于吲哚的 ATX 抑制剂。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，在减轻博来霉素暴露引起的受损肺组织方面表现出有希望的疗效。具有具体结合模式的新型含氨基甲酸酯的基于吲哚的 ATX 抑制剂可能有助于鉴定潜在的治疗剂以干预纤维化疾病。
