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

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.Toll样受体7（Toll-like receptor 7, TLR7）的异常激活被认为与自身免疫疾病高度相关。由于拮抗剂与人源Toll样受体7（HTLR7）的结合模式仍不明确，我们通过虚拟（in silico）技术构建了“开放构象”的HTLR7，以探究已知拮抗剂的通用结合模式。我们总结出TLR7拮抗剂的通用骨架，该骨架由三部分构成，并针对各部分提出了相应的设计策略。基于Q354侧链的柔性，我们提出了诱导型药效团弹头与非诱导型药效团弹头的概念，二者的对比分析阐明了与S1口袋形成疏水相互作用的重要性。最终，我们获得了一款基于咪唑并[1,2-a]吡啶的化合物44#，该化合物对TLR7具有良好的选择性，且展现出亚纳摩尔级的TLR7活性。在咪喹莫特诱导的银屑病小鼠模型中，两种剂量的44#均表现出良好的治疗效果。此外，44#可有效降低作为TLR7相关皮肤炎症关键调控因子的c-Rel的mRNA水平。