Identification of (6S)-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamines as new HBV capsid assembly modulators
Identification of (6S)-cyclopropyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamines as new HBV capsid assembly modulators
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(6S)-环丙基-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-甲胺作为新的 HBV 衣壳组装调节剂的鉴定
DOI：
10.1016/j.ejmech.2021.113974
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发表时间：
2022-01-15
影响因子：
6.7
通讯作者：
Liu, Mingliang
中科院分区：
文献类型：
--
作者：
Lv, Kai;Wu, Shuo;Liu, Mingliang
GYH 2 -18是由Roche INC.发现的具有6，7-二氢吡唑并[1，5-a]吡嗪-5（4 H）-甲酰胺（DPPC）骨架的II型HBV CAM。设计、合成了一系列GYH 2 -18衍生物，并对其抗HBV活性进行了评价。两个化合物2f和3 k显示出优异的抗HBV活性、低细胞毒性和可接受的口服PK特征。成功地对2f和3 k进行了手性分离，并鉴定了（6S）-环丙基DPPC异构体2f-1，2f-3，3 k-1和3 k-3的活性远高于相应的（6 R）-异构体。本文还对初步构效关系、粒子凝胶分析和分子模拟研究进行了讨论，为进一步合理设计新的（6S）-环丙基DPPC类似物提供了有益的指导。(c)2021 Elsevier Masson SAS。All rights reserved.
GYH2-18 is a type II HBV CAM with 6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamine (DPPC) skeleton discovered by Roche INC. A series of GYH2-18 derivatives were designed, synthesized and evaluated for their anti-HBV activity. Two compounds 2f and 3k exhibited excellent anti-HBV activity, low cytotoxicity and accepted oral PK profiles. Chiral separation of 2f and 3k was conducted successfully, and (6S)-cyclopropyl DPPC isomers 2f-1, 2f-3, 3k-1 and 3k-3 were identified to be much more active than the corresponding (6R)-ones. The preliminary structure-activity relationship, particle gel assay and molecular modeling studies were also discussed, which provide useful indications for guiding the further rational design of new (6S)-cyclopropyl DPPC analogues.(c) 2021 Elsevier Masson SAS. All rights reserved.