Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases

Toll-like receptor (TLR) 7 and TLR8 are endosomal sensorsof theinnate immune system that are activated by GU-rich single strandedRNA (ssRNA). Multiple genetic and functional lines of evidence linkchronic activation of TLR7/8 to the pathogenesis of systemic autoimmunediseases (sAID) such as Sjo''gren's syndrome (SjS) andsystemic lupus erythematosus (SLE). This makes targeting TLR7/8-inducedinflammation with small-molecule inhibitors an attractive approachfor the treatment of patients suffering from systemic autoimmune diseases.Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide).Its in vivo activity allows for further profilingtoward clinical trials in patients with autoimmune disorders, anda Phase 2 proof of concept study of MHV370 has been initiated, testingits safety and efficacy in patients with Sjo''gren's syndromeand mixed connective tissue disease.