The innate immune system employs toll-like receptors (TLRs) to identify signs of cellular stress and infection through the recognition of damage-associated and pathogen-associated molecular patterns, resulting in upregulation of immune pathways. Autoimmunity can result from the recognition of self motifs as foreign by the TLRs, with TLR7 and TLR8 being associated with human autoimmune diseases such as lupus, psoriasis, and arthritis. Our program to develop selective dual antagonists of TLR7/8 started with our previously reported indole scaffold substituted with a dimethoxyphenyl motif at C-2 and a piperidine at C-5. Elaboration of both the C-2 and C-5 regions aided by structure-based design led to indole analogs with bicyclic heteroaryl substituents at C-2 and substituted C-5 piperidines. Optimization of the C-2 bicyclic heteroarene, its peripheral substituents, and the C-5 piperidine substitution pattern each proved critical to the design of selective dual antagonists of TLR7/8 with progressible properties. One of the analogs discovered in our program, afimetoran, was selected as a development candidate and is currently in clinical trials for cutaneous lupus and systemic lupus (NCT04493541; NCT04895696). This poster will detail the explored SAR of the C-2 heteroarenes and C-5 piperidine substituents, and the in vivo performance for select analogs will be described.

Discovery of selective small-molecule dual antagonists of toll-like receptors 7 and 8 (TLR7/8) through optimization of an indole scaffold and C-2 bicyclic heteroarene substituents

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