Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect multiple tissues and organs including the joints, skin, and kidneys. Dysregulated activation of toll-like receptors 7 and 8 (TLR7/8) has been identified as contributing to the progression of SLE and other autoimmune disorders through the production of inflammatory cytokines, autoantibody generation, and activation of B cells and T cells. As part of our program focused on the identification of inhibitors of detrimental TLR7/8 signaling, which are anticipated to offer therapeutic benefit for SLE patients, we have previously described indole-based antagonists (1). X-ray co-crystallographic data with hTLR8 provided a structural understanding of the mode of inhibition of 1, guiding the genesis of the 1H-pyrazole-3-carboxamide core (2) as an alternative scaffold. Herein we disclose optimization of the 1H-pyrazoles in cellular and whole blood assays of TLR antagonism, as well as for pharmacokinetic properties, by replacing C-3 carboxamide with aromatic and heteroaromatic rings. The resulting leads (e.g., 3) demonstrated improved oral absorption, enabling their assessment in mouse pharmacodynamic assays to evaluate their ability to inhibit TLR7 signaling in vivo.

Identification of trisubstituted pyrazoles as potent and selective dual antagonists of toll-like receptors 7 and 8 (TLR 7/8) for the treatment of lupus

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.