The Discovery and Preclinical Profile of ALG-000184, a Prodrug of the Potent Hepatitis B Virus Capsid Assembly Modulator ALG-001075

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2024-11-22 DOI:10.1021/acs.jmedchem.4c01814

Sandrine Vendeville, Franck Amblard, Leda Bassit, Leonid N. Beigelman, Lawrence M. Blatt, Xiaoyuan Chen, Lang Chou, Dieudonné Buh Kum, Sushmita Chanda, Jerome Deval, Xiu Geng, Kusum Gupta, Andreas Jekle, Haiyang Hu, Xiaojuan Hu, Hyunsoon Kang, Cheng Liu, Jyanwei Liu, David C. McGowan, Dinah L. Misner, Pierre Raboisson, Abel Acosta Sanchez, Vladimir Serebryany, Antitsa D. Stoycheva, Julian A. Symons, Hua Tan, Hannah Vanrusselt, Caroline Williams, Michael Welch, Liangliang Zhang, Qingling Zhang, Yafeng Zhang, Raymond F. Schinazi, David B. Smith, Yannick Debing

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Abstract

Chronic hepatitis B (CHB) represents a significant unmet medical need with few options beyond lifelong treatment with nucleoside analogues, which rarely leads to a functional cure. Novel agents that reduce levels of HBV DNA, RNA and other viral antigens could lead to better treatment outcomes. The capsid assembly modulator (CAM) class of compounds represents an important modality for chronic suppression and to improve functional cure rates, either alone or in combination. GLP-26 is a potent CAM, which in this work was optimized for potency, safety, and other drug-like properties leading to ALG-001075. ALG-001075 was further advanced through clinical development as the highly soluble prodrug ALG-000184. ALG-000184 is currently being explored in multiple clinical trials in HBV-infected subjects where unprecedented reductions in HBV DNA, RNA and other viral antigens have been observed, making ALG-000184 a promising candidate to become a cornerstone for future chronic suppressive and combination treatment regimens for CHB.

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强效乙型肝炎病毒囊组装调节剂 ALG-001075 的原药 ALG-000184 的发现和临床前研究概况

慢性乙型肝炎（CHB）是一项尚未得到满足的重大医疗需求，除了使用核苷类似物进行终生治疗外，几乎没有其他选择，而核苷类似物很少能导致功能性治愈。降低 HBV DNA、RNA 和其他病毒抗原水平的新型药物可以带来更好的治疗效果。囊壳组装调节剂（CAM）类化合物是慢性抑制和提高功能性治愈率的重要方式，可以单独使用，也可以联合使用。GLP-26 是一种强效的 CAM，在这项研究中，GLP-26 的效力、安全性和其他类药物特性得到了优化，最终形成了 ALG-001075。ALG-001075 作为高溶性原药 ALG-000184 进一步推进了临床开发。目前，ALG-000184 正在多个临床试验中对 HBV 感染受试者进行探索，观察到 HBV DNA、RNA 和其他病毒抗原出现了前所未有的降低，这使得 ALG-000184 有希望成为未来慢性阻塞性肺结核慢性抑制和联合治疗方案的基石。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.