Discovery of Potent and Orally Bioavailable Pyrimidine Amide CGAS Inhibitors Via Structure-Guided Hybridization

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Dec 18

PMID 39691514

Authors

Patrick Cyr

Lee D Fader

Jason D Burch

Kelly A Pike

Daniel V Sietsema

Marc-Olivier Boily

Stephane Ciblat

Nicolas Sgarioto

Alexander M Skeldon

Samuel Gaudreault

Philippe Le Gros

Valerie Dumais

Daniel J J McKay

Nathan S Abraham

Ria Seliniotakis

Ramsay E Beveridge

Affiliations

Soon will be listed here.

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 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.

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