Journal of Medicinal Chemistry p. 3352 - 3371 (2017)
Update date:2022-08-16
Topics:
Qiu, Zongxing
Lin, Xianfeng
Zhang, Weixing
Zhou, Mingwei
Guo, Lei
Kocer, Buelent
Wu, Guolong
Zhang, Zhisen
Liu, Haixia
Shi, Houguang
Kou, Buyu
Hu, Taishan
Hu, Yimin
Huang, Mengwei
Yan, S. Frank
Xu, Zhiheng
Zhou, Zheng
Qin, Ning
Wang, Yue Fen
Ren, Shuang
Qiu, Hongxia
Zhang, Yuxia
Zhang, Yi
Wu, Xiaoyue
Sun, Kai
Zhong, Sheng
Xie, Jianxun
Ottaviani, Giorgio
Zhou, Yuan
Zhu, Lina
Tian, Xiaojun
Shi, Liping
Shen, Fang
Mao, Yi
Zhou, Xue
Gao, Lu
Young, John A. T.
Wu, Jim Zhen
Yang, Guang
Mayweg, Alexander V.
Shen, Hong C.
Tang, Guozhi
Zhu, Wei
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.
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