Several
toll-like receptors (TLRs) reside inside endosomes of specific
immune cellsamong them, aberrant activation of TLR7 and TLR9
is implicated in myriad contexts of autoimmune diseases, making them
promising therapeutic targets. However, small-molecule TLR7 and TLR9
antagonists are not yet available for clinical use. We illustrate
here the importance of C2, C6, and N9 substitutions in the purine
scaffold for antagonism to TLR7 and TLR9 through structure–activity
relationship studies using cellular reporter assays and functional
studies on primary human immune cells. Further in vitro and in vivo pharmacokinetic studies identified
an orally bioavailable lead compound 29, with IC50 values of 0.08 and 2.66 μM against TLR9 and TLR7,
respectively. Isothermal titration calorimetry excluded direct TLR
ligand–antagonist interactions. In vivo antagonism
efficacy against mouse TLR9 and therapeutic efficacy in a preclinical
murine model of psoriasis highlighted the potential of compound 29 as a therapeutic candidate in relevant autoimmune contexts.