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
收藏
页数：12
相关论文
共 50 条
  • [41] SYNTHESIS OF PYRROLO[2,3-D]PYRIMIDINE RIBOSIDES AND THEIR POTENTIAL IN CHEMOTHERAPEUTICS
    EGER, K
    GRIEB, G
    SPATLING, S
    JOURNAL OF HETEROCYCLIC CHEMISTRY, 1990, 27 (07) : 2069 - 2075
  • [42] Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors
    Magkrioti, Christiana
    Kaffe, Eleanna
    Stylianaki, Elli-Anna
    Sidahmet, Camelia
    Melagraki, Georgia
    Afantitis, Antreas
    Matralis, Alexios N.
    Aidinis, Vassilis
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2020, 21 (19) : 1 - 18
  • [43] Discovery of novel c-Met kinase inhibitors bearing a thieno[2,3-d]pyrimidine or furo[2,3-d]pyrimidine scaffold
    Zhao, Ailing
    Gao, Xin
    Wang, Yuanxiang
    Ai, Jing
    Wang, Ying
    Chen, Yi
    Geng, Meiyu
    Zhang, Ao
    BIOORGANIC & MEDICINAL CHEMISTRY, 2011, 19 (13) : 3906 - 3918
  • [44] Design, synthesis, antitumor evaluation, and molecular docking of novel pyrrolo[2,3-d]pyrimidine as multi-kinase inhibitors
    Alanazi, Ashwag S.
    Mirgany, Tebyan O.
    Alsaif, Nawaf A.
    Alsfouk, Aisha A.
    Alanazi, Mohammed M.
    SAUDI PHARMACEUTICAL JOURNAL, 2023, 31 (06) : 989 - 997
  • [45] Synthesis of classical, three carbon bridged 5-substituted furo[2,3-d]pyrimidine, and 6-substituted pyrrolo[2,3-d]pyrimidine analogs as antifolates.
    Gangjee, A
    Zeng, YB
    McGuire, JJ
    Kisliuk, RL
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2001, 222 : U651 - U651
  • [46] Pyrrolo[2,3-d]pyrimidines active as Btk inhibitors
    Musumeci, Francesca
    Sanna, Monica
    Greco, Chiara
    Giacchello, Ilaria
    Fallacara, Anna Lucia
    Amato, Rosario
    Schenone, Silvia
    EXPERT OPINION ON THERAPEUTIC PATENTS, 2017, 27 (12) : 1305 - 1318
  • [47] Synthesis of pyrrolo[2,3-d]pyridazinones as potent, subtype selective PDE4 inhibitors
    Giovannoni, Maria P.
    Cesari, Nicoletta
    Graziano, Alessia
    Vergelli, Claudia
    Biancalani, Claudio
    Biagini, Pierfrancesco
    Dal Piaz, Vittorio
    JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2007, 22 (03) : 309 - 318
  • [48] Design, synthesis and anti-inflammatory evaluation of novel pyrrolo [2,3-d] pyrimidin derivatives as potent JAK inhibitors
    Jiang, Feng
    Zang, Linghe
    Miao, Xiuqi
    Jia, Fang
    Wang, Jie
    Zhu, Minglin
    Gong, Ping
    Jiang, Nan
    Zhai, Xin
    BIOORGANIC & MEDICINAL CHEMISTRY, 2019, 27 (18) : 4089 - 4100
  • [49] Optical study of the formation of pyrrolo[2,3-d]pyrimidine-based fluorescent nanoaggregates
    Skardziute, Lina
    Kazlauskas, Karolis
    Dodonova, Jelena
    Bucevicius, Jonas
    Tumkevicius, Sigitas
    Jursenas, Saulius
    TETRAHEDRON, 2013, 69 (46) : 9566 - 9572
  • [50] Novel 5′-Norcarbocyclic Derivatives of Bicyclic Pyrrolo- and Furano[2,3-d]Pyrimidine Nucleosides
    Klimenko, Anna A.
    Matyugina, Elena S.
    Logashenko, Evgeniya B.
    Solyev, Pavel N.
    Zenkova, Marina A.
    Kochetkov, Sergey N.
    Khandazhinskaya, Anastasia L.
    MOLECULES, 2018, 23 (10):
12345