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

作者：Sandrine Vendeville, Franck Amblard, Leda Bassit, Leonid N. Beigelman, Lawrence M. Blatt, Xiaoyuan Chen, Lang Chou, Dieudonné Buh Kum, Sushmita Chanda, Jérôme Deval, Xiu Geng, Kusum Gupta, Andreas Jekle, Haiyang Hu, Xiaojuan Hu, Hyunsoon Kang, Cheng Liu, Jyanwei Liu, David C. McGowan, Dinah Misner, Pierre Raboisson, Abel Acosta Sanchez, V. N. Serebryany, Antitsa Stoycheva, Julian Symons, Hua Tan, Hannah Vanrusselt, Caroline Williams, Michael J. Welch, Liangliang Zhang, Qingling Zhang, Yafeng Zhang, Raymond F. Schinazi, David B. Smith, Yannick Debing · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c01814 · 被引用次数：26 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Bacteriophages and microbial interactions

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.