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.