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

• Published in: ACS medicinal chemistry letters Vol. 14; no. 8; pp. 1054 - 1062
• Main Authors: Alper, Phil, Betschart, Claudia, André, Cédric, Boulay, Thomas, Cheng, Dai, Deane, Jonathan, Faller, Michael, Feifel, Roland, Glatthar, Ralf, Han, Dong, Hemmig, Rene, Jiang, Tao, Knoepfel, Thomas, Maginnis, Jillian, Mutnick, Daniel, Pei, Wei, Ruzzante, Giulia, Syka, Peter, Zhang, Guobao, Zhang, Yi, Zink, Florence, Zipfel, Géraldine, Hawtin, Stuart, Junt, Tobias, Michellys, Pierre-Yves
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.08.2023; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; toll-like receptor 8; Toll-like receptor 7; innate immunity; SAR; lupus; RECOGNITION; TOLL-LIKE RECEPTORS
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00136

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.