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](/image/eyJ1cmkiOiJodHRwczovL3MzLWV1LXdlc3QtMS5hbWF6b25hd3MuY29tL3N0YWNrYWRlbWljL3Byb2R1Y3Rpb24vcGFwZXIvOTA2MjE3OC5wbmciLCJmb3JtYXQiOiJ3ZWJwIiwicXVhbGl0eSI6MTAwLCJub0NhY2hlIjp0cnVlfQ==.webp)
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.
Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523421008230
DOI: 10.1016/j.ejmech.2021.113974
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