title: Ester Prodrugs of IHVR-19029 with Enhanced Oral Exposure and Prevention of Gastrointestinal Glucosidase Interaction.
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 to6in the plasma and liver; while in human, the conversion occurred mainly in liver. An in vivo pharmacokinetic study in mice demonstrated that the tetrabutyrate prodrug8achieved the most improved overall exposure of6upon both oral and intravenous administration.
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Ma
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wu
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Xuexiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Yang
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Huagang
authors.initials: H
authors.lastname: Lu
authors.affiliation: Lam Drug Discovery Consulting LLC , Chadds Ford, Pennsylvania 19317, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lam
authors.affiliation: Institute of Medical Biotechnology, Chinese Academy of Medical Sciences , Beijing, China.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Genentech , South San Francisco, California 94080, United States.
authors.forename: Zhengyin
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: William
authors.initials: W
authors.lastname: Kinney
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Chang
authors.affiliation: Baruch S. Blumberg Institute , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Du
keywords: ER α-glucosidases I and II; Ester prodrug; N-alkyldeoxynojirimycin; antiviral