The toll-like receptors (TLRs) are a family of pattern recognition receptors utilized by the innate immune system for detection of molecules associated with infection and stress, resulting in immune upregulation. Recognition of self-motifs as foreign by TLRs leads to initiation and propagation of autoinflammation, and studies have shown an association of TLR7 and TLR8 signaling with disorders such as psoriasis, arthritis and lupus. Our program aimed at the development of family-selective TLR7/8 small molecule antagonists began with our previously reported 2-phenyl-indole chemical series. Structure-guided evolution of the C-2 fragment led to the design of fused heteroaromatic bicycles containing hydrogen bond acceptors appropriately positioned for key interactions in the TLR ligand binding sites. Extensive investigations were performed around the identity of the C-2 heteroaromatic bicycle, its attachment point to the indole core, and the composition and arrangement of additional substituents on the C-2 headpiece. Concurrent with this effort, we explored substitution patterns at C-5 of the indole. Proper balancing of both C-2 and C-5 substituents led to numerous analogs with promising properties for progression. One of the compounds identified in this effort, afimetoran, was nominated for development and is under investigation in clinical studies for the treatment of cutaneous lupus and systemic lupus. The activity and profiling for multiple series within the C-2 bicyclic heteroarenes will be presented, with in vivo performance detailed for select analogs.

Optimization of indole-based antagonists of toll-like receptors 7 and 8 (TLR7/8) through C-2 variations

ACS Spring 2022

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