Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.

Using a high-throughput screening (HTS) approach, a new GTP-site binding pyridine-carboxylate series of cGAS inhibitors was discovered. The biochemical potency of this new pyridine carboxylate series was improved 166-fold from the original hit to double-digit nanomolar levels using structure-based design insights, but the series was found to suffer from low permeability and low bioavailability. A structure-based hybridization of the metal-binding motifs of the pyridine carboxylate series and our previously disclosed tetrahydrocarboline GTP-site ligand identified pyrimidine amide compound . Compound is potent against both human and mouse cGAS isoforms and has a favorable pharmacokinetic (PK) profile in mice. Additionally, compound displayed a dose-dependent reduction in cGAMP production in a ConA pharmacodynamic mouse model of acute liver injury, demonstrating potential utility as an in vivo tool compound for further investigation of the cGAS pathway.