Michellys, Pierre-Yves, Pei, Wei, Zhang, Yi, Jiang, Tao, Han, Dong, Zhang, Guobao, Chang, Dai, Alper, Phillip, Mutnick, Daniel, Deane, Jonathan, Syka, Peter, Maginnis, Jillian, Junt, Tobias, Knoepfel, Thomas, Betschart, Claudia, Glatthar, Ralf, Feifel, Roland, Faller, Michael, Hemmig, Rene and Zink, Florence (2023) Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases. ACS medicinal chemistry letters, 14 (8). pp. 1054-1062. ISSN 1948-5875

Abstract

Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for 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 profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren's syndrome and mixed connective tissue disease.

Item Type:	Article
Date Deposited:	07 Oct 2023 00:45
Last Modified:	07 Oct 2023 00:45
URI:	https://oak.novartis.com/id/eprint/48414