VNRX-9945，一种有效的，广泛活性的衣壳组装调节剂，作为慢性乙型肝炎病毒感染治疗的临床候选药物

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-20 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00315

Bin Liu, Jiangchao Yao, Thomas Haimowitz, Christopher A Benetatos, Steven A Boyd, Stephen M Condon, Christopher J Burns, Andre White, Damodharan Lakshminarasimhan, Robert K Suto, Ozgur Cakici, Anthony S Drager, Susan G Emeigh Hart, Daniel C Pevear, Glen A Coburn

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引用次数: 0

摘要

靶向乙型肝炎病毒（HBV）的衣壳蛋白已成为开发新的抗病毒疗法的一种有前途的策略。在这项研究中，我们报告了一系列新的吡咯氧羧酰胺化合物作为阻断病毒复制的HBV衣壳组装调节剂（CAMs）的发现。通过重点结构-活性关系（SAR）优化过程，我们鉴定出化合物12 (VNRX-9945)，该化合物在体外对多种HBV基因型表现出优异而广泛的抗病毒活性，并且在多种物种中具有良好的药代动力学特征。此外，12个在腺相关病毒感染HBV （AAV-HBV）小鼠模型中表现出强大的疗效。该化合物已进入1期临床试验，以评估其在健康志愿者中的安全性和药代动力学，从而能够治疗慢性HBV感染。

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Discovery of VNRX-9945, a Potent, Broadly Active Capsid Assembly Modulator as a Clinical Candidate for the Treatment of Chronic Hepatitis B Virus Infection.

Targeting the capsid protein of the hepatitis B virus (HBV) has emerged as a promising strategy for developing new antiviral therapies. In this study, we report the discovery of a novel series of pyrrole oxo-carboxamide compounds as HBV capsid assembly modulators (CAMs) that block viral replication. Through a process of focused structure-activity relationship (SAR) optimization, we identified compound 12 (VNRX-9945), which exhibited excellent and broad antiviral activity against multiple HBV genotypes in vitro, along with favorable pharmacokinetic profiles across multiple species. Additionally, 12 demonstrated robust efficacy in the adeno-associated virus mouse model of HBV (AAV-HBV) infection. This compound has advanced into Phase 1 clinical trials to evaluate its safety and pharmacokinetics in healthy volunteers, to enable treatment of chronic HBV infections.

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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.