Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors

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• 作者：Zongxing Qiu ; Xianfeng Lin ; Mingwei Zhou ; Yongfu Liu ; Wei Zhu ; Wenming Chen ; Weixing Zhang ; Lei Guo ; Haixia Liu ; Guolong Wu ; Mengwei Huang ; Min Jiang ; Zhiheng Xu ; Zheng Zhou ; Ning Qin ; Shuang Ren ; Hongxia Qiu ; Sheng Zhong ; Yuxia Zhang ; Yi Zhang ; Xiaoyue Wu ; Liping Shi ; Fang Shen ; Yi Mao ; Xue Zhou ; Wengang Yang ; Jim Z. Wu ; Guang Yang ; Alexander V. Mayweg ; Hong C. Shen ; Guozhi Tang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7651-7666
• 全文大小：767K
• 年卷期：0
• ISSN：1520-4804

文摘

Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV viruses. We carried out multidimensional structural optimizations based on the heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) and identified a novel series of HBV capsid inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, and in vitro safety profiles. Herein we disclose the design, synthesis, structure–activity relationship (SAR), cocrystal structure in complex with HBV capsid proteins and in vivo pharmacological study of the 4-methyl HAP analogues. In particular, the (2S,4S)-4,4-difluoroproline substituted analogue 34a demonstrated high oral bioavailability and liver exposure and achieved over 2 log viral load reduction in a hydrodynamic injected (HDI) HBV mouse model.