Design, Synthesis, and Biological Evaluation of new Toll-like Receptor 7 Agonists

Abstract

Toll-like receptor 7 (TLR7) is a potent target for treatment of various diseases such as viral infections, autoimmune disorders, or cancer immunotherapy. However, selectively activating TLR7 over TLR8 is challenging due to the structural similarity between the two receptors. Here, a novel series of potent and selective Toll-like receptor 7 (TLR7) agonists with low nanomolar in vitro activity were discovered. Starting from hit compound 10e, analogues were designed and synthesized for enhanced TLR7 activation through structure-activity relationship (SAR) study. Among the derivatives, compound 27b and 27d showed the strongest in vitro activity in low nanomolar range and induced IL-6 and TNF- α successfully in mouse macrophage. Our study opens new therapeutic possibilities for treating diseases that need potent immunomodulatory activity and selectivity.