Download MendeleyDiscovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.
Cyr, P., Fader, L.D., Burch, J.D., Pike, K.A., Sietsema, D.V., Boily, M.O., Ciblat, S., Sgarioto, N., Skeldon, A.M., Gaudreault, S., Le Gros, P., Dumais, V., McKay, D.J.J., Abraham, N.S., Seliniotakis, R., Beveridge, R.E.(2024) ACS Med Chem Lett 15: 2201-2209
- PubMed: 39691514
- DOI: https://doi.org/10.1021/acsmedchemlett.4c00471
- Primary Citation of Related Structures:
9ELX, 9MDC, 9MDD - PubMed 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-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.
Organizational Affiliation:
Ventus Therapeutics, 4800 rue Lévy #110, Saint-Laurent H4R 2P1, Quebec, Canada.
