1446680-75-6Relevant articles and documents
Design and synthesis of orally bioavailable 4-methyl heteroaryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors
Qiu, Zongxing,Lin, Xianfeng,Zhou, Mingwei,Liu, Yongfu,Zhu, Wei,Chen, Wenming,Zhang, Weixing,Guo, Lei,Liu, Haixia,Wu, Guolong,Huang, Mengwei,Jiang, Min,Xu, Zhiheng,Zhou, Zheng,Qin, Ning,Ren, Shuang,Qiu, Hongxia,Zhong, Sheng,Zhang, Yuxia,Zhang, Yi,Wu, Xiaoyue,Shi, Liping,Shen, Fang,Mao, Yi,Zhou, Xue,Yang, Wengang,Wu, Jim Z.,Yang, Guang,Mayweg, Alexander V.,Shen, Hong C.,Tang, Guozhi
, p. 7651 - 7666 (2016/09/04)
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, structureactivity 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.
4,4-DISUBSTITUTED-1,4-DIHYDROPYRIMIDINES AND THE USE THEREOF AS MEDICAMENTS FOR THE TREATMENT OF HEPATITIS B
-
Page/Page column 117, (2013/07/19)
Inhibitors of HBV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein R1-R5, B and Z have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HBV inhibitors, in HBV therapy.
