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

共 50 条

[31] Synthesis and anticancer evaluation of novel pyrrole-pyrido[2,3-d] pyrimidine-based compounds as thymidylate synthase inhibitors [J].

Kumar, Adarsh ;

Singh, Ankit Kumar ;

Singh, Harshwardhan ;

Debbaraman, Tanushree ;

Pathak, Prateek ;

Naumovich, Vladislav ;

Grishina, Maria ;

Kumar, Pradeep .

JOURNAL OF MOLECULAR STRUCTURE, 2025, 1336

[32] Identification of Substituted Naphthotriazolediones as Novel Tryptophan 2,3-Dioxygenase (TDO) Inhibitors through Structure-Based Virtual Screening [J].

Wu, Jian-Sung ;

Lin, Shu-Yu ;

Liao, Fang-Yu ;

Hsiao, Wen-Chi ;

Lee, Lung-Chun ;

Peng, Yi-Hui ;

Hsieh, Chia-Ling ;

Wu, Mine-Hsine ;

Song, Jen-Shin ;

Yueh, Andrew ;

Chen, Chun-Hwa ;

Yeh, Shiu-Hwa ;

Liu, Chia-Yeh ;

Lin, Shu-Yi ;

Yeh, Teng-Kuang ;

Hsu, John T. -A. ;

Shih, Chuan ;

Ueng, Shau-Hua ;

Hung, Ming-Shiu ;

Wu, Su-Ying .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (19) :7807-7819

[33] Discovery of new VEGFR-2 inhibitors and apoptosis inducer-based thieno[2,3-d]pyrimidine [J].

El-Metwally, Souad A. ;

Elkady, Hazem ;

Hagras, Mohamed ;

Elkaeed, Eslam B. ;

Alsfouk, Bshra A. ;

Doghish, Ahmed S. ;

Ibrahim, Ibrahim M. ;

Taghour, Mohammed S. ;

Husein, Dalal Z. ;

Metwaly, Ahmed M. ;

Eissa, Ibrahim H. .

FUTURE MEDICINAL CHEMISTRY, 2023, 15 (22) :2065-2086

[34] Concise synthesis of pyrrolo[2,3-d]pyrimidine derivatives via the Cu-catalyzed coupling reaction [J].

Wang, Leilei ;

Zheng, Liwen ;

Kong, Xue ;

Zhang, Wen ;

Chen, Guanhong ;

Wang, Jianing .

GREEN CHEMISTRY LETTERS AND REVIEWS, 2017, 10 (01) :42-47

[35] Hit Selection of Dipeptidyl Peptidase-4 Inhibitors Bearing Thieno[2,3-d]Pyrimidine Scaffold [J].

Pavlovic, Katarina Tomovic ;

Ilic, Budimir S. ;

Dimov, Stefan ;

Yancheva, Denitsa ;

Mavrova, Anelia Ts ;

Smelcerovic, Andrija .

CHEMISTRY & BIODIVERSITY, 2025, 22 (05)

[36] Synthesis and biological evaluation of 1H-pyrrolo[2,3-d]pyrimidine-1,2,3-triazole derivatives as novel anti-tubercular agents [J].

Rain, Kasa Shiva ;

Ankireddy, Sandeep ;

Sabitha, Gowravaram ;

Krishna, Vagolu Siva ;

Sriram, Dharmarajan ;

Reddy, Kunduru Bharathi ;

Sagurthi, Someswar Rao .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2019, 29 (02) :284-290

[37] Design, Synthesis, and biological evaluation of 7H-Pyrrolo[2,3-d] pyrimidines as potent HPK1 kinase inhibitors [J].

Wu, Feifei ;

Li, Huiyu ;

Li, Weiqiang ;

Zhang, Laishun ;

An, Qi ;

Sun, Jiaqi ;

Zhang, Qian ;

Sun, Yaoliang ;

Xu, Lei ;

Yu, Jinghua ;

Diao, Xingxing ;

Li, Jia ;

Meng, Linghua ;

Xu, Shilin .

BIOORGANIC & MEDICINAL CHEMISTRY, 2025, 119

[38] Synthesis, biological evaluation and docking studies of new pyrrolo[2,3-d] pyrimidine derivatives as Src family-selective tyrosine kinase inhibitors [J].

Dincer, Sebla ;

Cetin, Kadir Taylan ;

Onay-Besikci, Arzu ;

Olgen, Sureyya .

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2013, 28 (05) :1080-1087

[39] Structure-based identification of potent VEGFR-2 inhibitors from in vivo metabolites of a herbal ingredient [J].

Dash, Raju ;

Junaid, Md. ;

Mitra, Sarmistha ;

Arifuzzaman, Md ;

Hosen, S. M. Zahid .

JOURNAL OF MOLECULAR MODELING, 2019, 25 (04)

[40] Structure-based identification of potent VEGFR-2 inhibitors from in vivo metabolites of a herbal ingredient [J].

Raju Dash ;

Md. Junaid ;

Sarmistha Mitra ;

Md Arifuzzaman ;

S. M. Zahid Hosen .

Journal of Molecular Modeling, 2019, 25

← 1 2 3 4 5 →