Reducing hERG Inhibition in the Design of Potent and Bioavailable Indazole cGAS Inhibitors

Cyclic GMP-AMP synthase (cGAS) is a key component of the cGAS-STING innate immunity pathway’s response to pathogens. Activation of cGAS triggers a cascade resulting in an increase of proinflammatory mediators, suggesting cGAS inhibition as an attractive therapeutic approach for a variety of autoimmune and neurodegenerative diseases. The medicinal chemistry optimization of tetrahydrocarboline cGAS inhibitor 3 was performed with particular emphasis on mitigating hERG activity and improving bioavailability. Meticulous control of polarity was found to be essential to access acceptable in vitro permeability and stability profiles while mitigating hERG inhibition. Compound 26 was identified as a potent cGAS inhibitor displaying favorable hERG and mouse pharmacokinetic (PK) profiles.