A screen for small-molecule antagonists of Toll-like receptor 9 (TLR9) uncovered a triazine chemotype hit with potential liabilities, including a nitroarene, a hydrazone, and a free phenol. Systematic replacement of these liabilities led to the identification of compound 20, which maintained submicromolar TLR9 antagonism while exhibiting oral bioavailability and robust pharmacodynamic effects in a bleomycin-induced lung fibrosis model.
Mandler et al. (2026) studied this question.