A primary defect in lupus patients is the accumulation of apoptotic debris enriched in RNA ligands capable of activating TLR7 and TLR8, especially as the ligands form immune complexes with pre-existing autoantibodies. TLR7/8 belong to the toll-like receptor class of proteins which play a key role in recognizing structurally conserved molecules derived from potential pathogens or from cellular debris. They are single-pass, membrane-spanning, non-catalytic receptors expressed in cells such as B-cells, macrophages and dendritic cells. Stimulation of TLR7/8 within these cells leads to initiation of innate immune responses that includes secretion of proinflammatory cytokines and chemokines and the production of Type I interferons. As dysregulated TLR signaling has been implicated in several autoimmune/inflammatory diseases such as lupus, inhibitors of TLR7/8 are anticipated to offer therapeutic benefit for patients with this disease. In this communication we describe the structure-guided design of TLR7/8 antagonists based on a pyrrolothiazole motif as a highly effective replacement for an indole scaffold. Optimization of this series for potent and balanced dual inhibition of TLR7/8, with excellent selectivity among other TLR family members will be presented, along with pharmacokinetic evaluation and performance in a mouse pharmacodynamic model for TLR7 inhibition. The structural basis for inhibition of this series, based on X-ray co-crystal structures, will be detailed.

Optimization of 4H-pyrrolo[3,2-d]thiazole based antagonists of toll-like receptors 7 and 8 (TLR7/8) for the treatment of lupus

ACS Spring 2022

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