| 標題: | Development of Isoquinolinone Derivatives as Potential HCV NS5B Polymerase Inhibitors |
| 作者: | Ravindra R. Deore
Grace S. Chen
Chien-Shu Chen
Pei-The Chang
Ji-Wang Chern |
| 日期: | 2011 |
| 上傳時間: | 2011-06-23 14:56:48 (UTC+8) |
| 摘要: | NS5B RNA dependent RNA polymerase plays a crucial role in HCV replication and it has no counterpart in mammalian cells. Therefore, it is popularly regarded as a potential drug target for the treatment of HCV infections. The design, synthesis andSAR of quinazolinone derivatives as NS5B inhibitors will be discussed. Structural optimization of this series revealed that compound J017171 possess highest potency (IC50 = = 9.5 uM) to to inhibit NS5B activity based on the inorganic pyrophosphate generation and also demonstrated goo0d potency (IC5o = 5.9 uM) in another assay method based on NTP incorporation by NS5B enzyme. J017171 demonstrated moderate cytotoxicity (IC50 =15.7 uM) to HCV genotype lb replicon containing Ava5 cells. NMR and UV studies have shown that J017171 forms stable chelates with the Mg2+ ions in vitro. Molecular docking confirms that J017171 forms chelating interactions with two Mg2+ ions in the active site of enzyme. |
| 關聯: | 2011年台俄有機、藥物與生物化學交流暨藥物化學研討會，起迄日：2011/04/06~2011/04/05，地點：溪頭台大實驗林 |
| Appears in Collections: | [藥理學院] 2011年台俄有機、藥物與生物化學交流暨藥物化學研討會
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