Ester Prodrugs of IHVR-19029 with Enhanced Oral Exposure and Prevention of Gastrointestinal Glucosidase Interaction

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• 作者：Julia Ma ; Shuo Wu ; Xuexiang Zhang ; Fang Guo ; Katherine Yang ; Jia Guo ; Qing Su ; Huagang Lu ; Patrick Lam ; Yuhuan Li ; Zhengyin Yan ; William Kinney ; Ju-Tao Guo ; Timothy M. Block ; Jinhong Chang ; Yanming Du
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：8
• 期：2
• 页码：157-162
• 全文大小：354K
• ISSN：1948-5875

文摘

IHVR-19029 (6) is a lead endoplasmic reticulum α-glucosidases I and II inhibitor, which efficiently protected mice from lethal Ebola and Marburg virus infections via injection route, but suffered from low bioavailability and off-target interactions with gut glucosidases when administered orally. In an effort to improve efficacious exposure levels and avoid side effects, we designed and synthesized ester prodrugs. Not only were the prodrugs stable in simulated gastric and intestinal fluids and were inactive against glucosidases but they also exhibited antiviral activities against dengue virus infection in a cell based assay. Further in vitro evaluation showed that the bioconversion of the prodrugs is species dependent: in mice, the prodrugs were converted to 6 in the plasma and liver; while in human, the conversion occurred mainly in liver. An in vivo pharmacokinetic study in mice demonstrated that the tetrabutyrate prodrug 8 achieved the most improved overall exposure of 6 upon both oral and intravenous administration.