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.

GYH2-18是罗氏公司发现的具有6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-甲胺(DPPC)骨架的II型HBV CAM。设计、合成了一系列GYH2-18衍生物并评估其抗HBV活性。两种化合物2f和3k表现出优异的抗 HBV 活性、低细胞毒性和可接受的口服 PK 曲线。成功进行了2f和3k的手性分离，发现 (6 S )-环丙基 DPPC 异构体​​ 2f-1、2f-3、3k-1和3k-3比相应的 (6 R）-那些。还讨论了初步构效关系、颗粒凝胶测定和分子建模研究，为指导进一步合理设计新型( 6S )-环丙基DPPC类似物提供了有益的指导。