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.
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页数：12
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