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

• Published in: ACS medicinal chemistry letters Vol. 15; no. 12; pp. 2201 - 2209
• Main Authors: Cyr, Patrick, Fader, Lee D., Burch, Jason D., Pike, Kelly A., Sietsema, Daniel V., Boily, Marc-Olivier, Ciblat, Stéphane, Sgarioto, Nicolas, Skeldon, Alexander M., Gaudreault, Samuel, Le Gros, Philippe, Dumais, Valérie, McKay, Daniel J. J., Abraham, Nathan S., Seliniotakis, Ria, Beveridge, Ramsay E.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.12.2024; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; autoimmune diseases; cGAS; cGAMP; hybridization; inflammation; GENE; DNA; TREX1
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.4c00471

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-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.