铅化合物
化学
嘧啶
配体效率
体内
药理学
羧酸盐
酰胺
结合位点
结构-活动关系
立体化学
生物化学
配体(生物化学)
体外
生物
受体
生物技术
作者
Patrick Cyr,L. D. Fader,Jason D. Burch,Kelly A. Pike,Daniel V. Sietsema,Marc-Olivier Boily,Stéphane Ciblat,Nicolas Sgarioto,Alexander Skeldon,Samuel Gaudreault,Pierre Gros,Valérie Dumais,Daniel J. McKay,Nathan S. Abraham,Ria Seliniotakis,Ramsay E. Beveridge
标识
DOI:10.1021/acsmedchemlett.4c00471
摘要
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.
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