Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus,Journal of Medicinal Chemistry

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Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-10-06 , DOI: 10.1021/acs.jmedchem.3c01145
Buyu Kou _{1,

2} , Zhisen Zhang _{1,

2} , Xingchun Han _{1,

2} , Zheng Zhou _{2,

3} , Zhiheng Xu _{2,

3} , Xue Zhou _{1,

4} , Fang Shen _{1,

4} , Yuan Zhou _{1,

4} , Xiaojun Tian _{1,

4} , Guang Yang _{1,

4} , John A T Young _{4,

5} , Hongxia Qiu _{1,

6} , Giorgio Ottaviani _{1,

6} , Alexander Mayweg _{2,

5} , Wei Zhu _{1,

2} , Hong C Shen _{1,

2} , Haixia Liu _{1,

2} , Taishan Hu _{1,

2}

Affiliation

Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.

中文翻译：

发现 4,5,6,7-四氢吡唑并[1.5-a]吡嗪衍生物作为抑制乙型肝炎病毒的核心蛋白变构调节剂 (CpAM)

乙型肝炎病毒 (HBV) 核心蛋白变构调节剂 (CpAM) 是一类颇具吸引力的潜在抗 HBV 治疗药物。在这里，我们描述了一系列 4,5,6,7-四氢吡唑并[1,5- a ]吡嗪 (THPP) 化合物作为 HBV CpAM 的发现工作，这些化合物可有效抑制广泛的核苷抗性乙型肝炎病毒变异体。在 HBV AAV 小鼠模型中，先导化合物45通过口服给药可抑制 HBV DNA 病毒载量。

更新日期：2023-10-06

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