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

ABSTRACT: 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 23 identified pyrimidine amide compound 36. Compound 36 is potent against both human and mouse cGAS isoforms and has a favorable pharmacokinetic (PK) profile in mice. Additionally, compound 36 displayed a dose-depe

SUBMITTER: Cyr P 

PROVIDER: S-EPMC11647726 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature