A Chemical Switch for Transforming a Purine Agonist for Toll-like Receptor 7 to a Clinically Relevant Antagonist

Toll-like receptor 7 (TLR7) is an established therapeutic target
in myriad autoimmune disorders, but no TLR7 antagonist is available
for clinical use to date. Herein, we report a purine scaffold TLR7
antagonist, first-of-its-kind to our knowledge, which was developed
by rationally dissecting the structural requirements for TLR7-targeted
activity for a purine scaffold. Specifically, we identified a singular
chemical switch at C-2 that could make a potent purine scaffold TLR7
agonist to lose agonism and acquire antagonist activity, which could
further be potentiated by the introduction of an additional basic
center at C-6. We ended up developing a clinically relevant TLR7 antagonist
with favorable pharmacokinetics and 70.8% oral bioavailability in
mice. Moreover, the TLR7 antagonists depicted excellent selectivity
against TLR8. To further validate the in vivo applicability
of this novel TLR7 antagonist, we demonstrated its excellent efficacy
in preventing TLR7-induced pathology in a preclinical murine model
of psoriasis.