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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 eCollection Date: 2024-12-12 DOI:10.1021/acsmedchemlett.4c00471

Patrick Cyr, Lee D Fader, Jason D Burch, Kelly A Pike, Daniel V Sietsema, Marc-Olivier Boily, Stéphane Ciblat, Nicolas Sgarioto, Alexander M Skeldon, Samuel Gaudreault, Philippe Le Gros, Valérie Dumais, Daniel J J McKay, Nathan S Abraham, Ria Seliniotakis, Ramsay E Beveridge

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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.

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通过结构引导杂交发现有效和口服的嘧啶酰胺cGAS抑制剂。

采用高通量筛选（HTS）方法，发现了一个新的gtp位点结合吡啶-羧酸酯系列cGAS抑制剂。利用基于结构的设计见解，这种新的吡啶羧酸盐系列的生化效能从原来的水平提高了166倍，达到了两位数的纳摩尔水平，但该系列被发现存在低渗透性和低生物利用度的问题。对吡啶羧酸酯系列的金属结合基序和我们之前公开的四碳氢化合物gtp位点配体23进行了基于结构的杂交，鉴定出嘧啶酰胺化合物36。化合物36对人和小鼠cGAS亚型均有效，在小鼠体内具有良好的药代动力学（PK）谱。此外，在急性肝损伤的ConA药效学小鼠模型中，化合物36显示出cGAMP产生的剂量依赖性减少，表明了作为进一步研究cGAS途径的体内工具化合物的潜在效用。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.