Structure-based identification of novel pyrrolo[2,3-d]pyrimidine analogs as potent autotaxin inhibitors

被引：0

作者：

Wei, Shangfei ^{[1
]}

Liu, Nan ^{[2
]}

Zhou, Cong ^{[1
]}

Guo, Mengrao ^{[1
]}

Ma, Deyi ^{[1
]}

Lei, Hongrui ^{[1
]}

Zhai, Xin ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China

[2] Shenyang Pharmaceut Univ, Sch Pharm, Shenyang 110016, Peoples R China

来源：

JOURNAL OF MOLECULAR STRUCTURE | 2025年 / 1331卷

基金：

中国国家自然科学基金;

关键词：

Autotaxin inhibitor; Pyrrolo[2,3-d ]pyrimidine; Design & synthesis; Molecular docking; DISCOVERY; BINDING; PLASMA;

D O I：

10.1016/j.molstruc.2025.141573

中图分类号：

O64 [物理化学（理论化学）、化学物理学];

学科分类号：

070304 ; 081704 ;

摘要：

In recent decades, it has been well established that the down-regulation of the autotaxin-lysophosphatidic acid (ATX-LPA) signaling pathway showed considerable effectiveness in treating various diseases. In order to develop novel potent ATX inhibitors, a series of pyrrolo[2,3-d]pyrimidine derivatives (G1 similar to G22) were designed and synthesized based on the molecular docking of PAT-409 with ATX protein. All compounds were selected for ATX inhibitory activity studies in vitro to extend the structure-activity relationship (SAR) study. To our delight, some compounds displayed preferable activity against ATX enzyme. Among them, compound G18 with a typical N-4-(hydroxyphenyl)acetamide hydrophilic "tail" showed the most excellent activity against ATX with IC50 values of 8.1 nM, exceeding that of PAT-409 (IC50 = 9.8 nM). Meanwhile, G18 was endowed with superior druglikeness properties, making it a promising therapeutic agent for the treatment of ATX-driven diseases.

引用

页数：12

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