2. Academic Validation
  3. Rational Design of Imidazo[1,2- a]pyridine as an Effective TLR7 Antagonist for the Treatment of Psoriasis: Research Combined with In Silico Study

Rational Design of Imidazo[1,2- a]pyridine as an Effective TLR7 Antagonist for the Treatment of Psoriasis: Research Combined with In Silico Study

  • J Med Chem. 2026 Mar 12;69(5):5309-5349. doi: 10.1021/acs.jmedchem.5c02121.
Peng Yao 1 2,  Xing Li 1,  Guisen Li 1 3,  Mingge Song 1 3,  Tianming Yu 4,  Zuguo Zheng 1,  Yue Zhao 5,  Jiaxing Li 1 3,  Dawei Wang 1 3,  Yasheng Zhu 1 3,  Yi Hou 1 3,  Jiayu Ding 1 3,  Hao Shen 1 3,  Guoyu Zhang 1 3,  Meijie Ji 1 3,  Hua Yang 2,  Ping Li 1,  Zhihong Liu 5,  Peng Yang 1 3 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 School of Science, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 4 School of Systems Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China.
  • 5 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.
  • 6 Institute of Innovative Drug, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41708477 DOI: 10.1021/acs.jmedchem.5c02121
Abstract

The abnormal activation of TLR7 is considered to be highly correlated with autoimmune diseases. Since the binding mode of antagonists and HTLR7 is still unclear, we constructed an "opened-form" HTLR7 in silico to explore the common binding mode of known antagonists. A general skeleton was summarized for the TLR7 Antagonist, which consists of three parts, and design strategies for them were proposed. Moreover, based on the flexibility of the Q354 side chain, the concepts of induced and noninduced warheads were put forward, while the comparison of them elucidated the importance of forming hydrophobic interactions with the S1 pocket. Finally, an imidazo[1,2-a]pyridine-based compound, 44#, was obtained, which achieves selectivity toward TLR7 and subnanomolar potency on TLR7. In the imiquimod-induced psoriasis mice model, both doses of 44# showed good therapeutic effects. In addition, 44# effectively reduced the mRNA level of c-Rel, which acts as a key regulator of TLR7-related skin inflammation.

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