| Literature DB >> 27458651 |
Zongxing Qiu1, Xianfeng Lin1, Mingwei Zhou1, Yongfu Liu1, Wei Zhu1, Wenming Chen1, Weixing Zhang1, Lei Guo1, Haixia Liu1, Guolong Wu1, Mengwei Huang1, Min Jiang1, Zhiheng Xu1, Zheng Zhou1, Ning Qin1, Shuang Ren1, Hongxia Qiu1, Sheng Zhong1, Yuxia Zhang1, Yi Zhang1, Xiaoyue Wu1, Liping Shi1, Fang Shen1, Yi Mao1, Xue Zhou1, Wengang Yang1, Jim Z Wu1, Guang Yang1, Alexander V Mayweg1, Hong C Shen1, Guozhi Tang1.
Abstract
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.Entities:
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Year: 2016 PMID： 27458651 DOI： 10.1021/acs.jmedchem.6b00879
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446