| Literature DB >> 28339215 |
Zongxing Qiu1, Xianfeng Lin1, Weixing Zhang1, Mingwei Zhou1, Lei Guo1, Buelent Kocer1, Guolong Wu1, Zhisen Zhang1, Haixia Liu1, Houguang Shi1, Buyu Kou1, Taishan Hu1, Yimin Hu1, Mengwei Huang1, S Frank Yan1, Zhiheng Xu1, Zheng Zhou1, Ning Qin1, Yue Fen Wang1, Shuang Ren1, Hongxia Qiu1, Yuxia Zhang1, Yi Zhang1, Xiaoyue Wu1, Kai Sun1, Sheng Zhong1, Jianxun Xie1, Giorgio Ottaviani1, Yuan Zhou1, Lina Zhu1, Xiaojun Tian1, Liping Shi1, Fang Shen1, Yi Mao1, Xue Zhou1, Lu Gao1, John A T Young1, Jim Zhen Wu1, Guang Yang1, Alexander V Mayweg1, Hong C Shen1, Guozhi Tang1, Wei Zhu1.
Abstract
Described herein are the discovery and structure-activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug-like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen bonding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further development as oral anti-HBV infection agent.Entities:
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Year: 2017 PMID： 28339215 DOI： 10.1021/acs.jmedchem.7b00083
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446