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Journal article
Ester Prodrugs of IHVR-19029 with Enhanced Oral Exposure and Prevention of Gastrointestinal Glucosidase Interaction
ACS medicinal chemistry letters, v 8(2), pp 157-162
09 Feb 2017
PMID: 28197304
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
Metrics
Details
- Title
- Ester Prodrugs of IHVR-19029 with Enhanced Oral Exposure and Prevention of Gastrointestinal Glucosidase Interaction
- Creators
- Julia Ma - Baruch S. Blumberg InstituteShuo Wu - Baruch S. Blumberg InstituteXuexiang Zhang - Baruch S. Blumberg InstituteFang Guo - Baruch S. Blumberg InstituteKatherine Yang - University of MichiganJia Guo - Baruch S. Blumberg InstituteQing Su - Baruch S. Blumberg InstituteHuagang Lu - Baruch S. Blumberg InstitutePatrick Lam - Lam Drug Discovery Consulting LLCYuhuan Li - Chinese Academy of Medical SciencesZhengyin Yan - Genentech, South San Francisco, California 94080, United StatesWilliam Kinney - Baruch S. Blumberg InstituteJu-Tao Guo - Baruch S. Blumberg InstituteTimothy M. Block - Baruch S. Blumberg InstituteJinhong Chang - Baruch S. Blumberg InstituteYanming Du - Baruch S. Blumberg Institute
- Publication Details
- ACS medicinal chemistry letters, v 8(2), pp 157-162
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Pharmacology and Physiology
- Web of Science ID
- WOS:000393938900005
- Scopus ID
- 2-s2.0-85013764661
- Other Identifier
- 991020547608004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal