| Autor: |
Wang, Chunting, Pei, Yameng, Wang, Lin, Li, Shuo, Jiang, Chao, Tan, Xu, Dong, Yi, Xiang, Ye, Ma, Yao, Liu, Gang |
| Zdroj: |
Journal of Medicinal Chemistry; June 2020, Vol. 63 Issue: 11 p6066-6089, 24p |
| Abstrakt: |
Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56with an EC50value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56did not show in vivoanti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs. |
| Databáze: |
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