Ester Prodrugs of IHVR-19029 with Enhanced Oral Exposure and Prevention of Gastrointestinal Glucosidase Interaction
| Autor: | William A. Kinney, Julia Ma, Shuo Wu, Jinhong Chang, Ju-Tao Guo, Huagang Lu, Xuexiang Zhang, Fang Guo, Yanming Du, Zhengyin Yan, Katherine Yang, Jia Guo, Lam Patrick Y S, Qing Su, Timothy M. Block, Yu-Huan Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
biology Chemistry Endoplasmic reticulum Organic Chemistry Prodrug Pharmacology Dengue virus medicine.disease_cause Biochemistry In vitro Bioavailability 03 medical and health sciences 030104 developmental biology Pharmacokinetics In vivo Drug Discovery biology.protein medicine Glucosidases |
| Popis: | 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 a... |
| Databáze: | OpenAIRE |
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