Inappropriate activation of TLR7 and TLR8 is linked to several autoimmune diseases, such as lupus erythematosus. Here we report on the efficient structure-based optimization of the inhibition of TLR8, starting from a co-crystal structure of a small screening hit. Further optimization of the physicochemical properties for cellular potency and expansion of the structure-activity relationship for dual potency finally resulted in a highly potent TLR7/8 antagonist with demonstrated efficacy after oral dosing.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014506 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.1c00696 | DOI Listing |
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