Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs
Author(s)
Golder, Matthew R; Liu, Jenny; Andersen, Jannik N.; Shipitsin, Michail V.; Vohidov, Farrukh; Nguyen, Hung V.-T.; Ehrlich, Deborah C.; Huh, Sung Jin; Vangamudi, Bhavatarini; Economides, Kyriakos D.; Neenan, Allison M.; Ackley, James C.; Baddour, Joelle; Paramasivan, Sattanathan; Brady, Samantha W.; Held, Eric J.; Reiter, Lawrence A.; Saucier-Sawyer, Jennifer K.; Kopesky, Paul W.; Chickering, Donald E.; Blume-Jensen, Peter; Johnson, Jeremiah A.; ... Show more Show less
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At present there are no drugs for the treatment of chronic liver fibrosis that have been approved by the Food and Drug Administration of the United States. Telmisartan, a small-molecule antihypertensive drug, displays antifibrotic activity, but its clinical use is limited because it causes systemic hypotension. Here, we report the scalable and convergent synthesis of macromolecular telmisartan prodrugs optimized for preferential release in diseased liver tissue. We have optimized the release of active telmisartan in fibrotic liver to be depot-like (that is, a constant therapeutic concentration) through the molecular design of telmisartan brush-arm star polymers, and show that these lead to improved efficacy and to the avoidance of dose-limiting hypotension in both metabolically and chemically induced mouse models of hepatic fibrosis, as determined by histopathology, enzyme levels in the liver, intact-tissue protein markers, hepatocyte necrosis protection and gene-expression analyses. In rats and dogs, the prodrugs are retained long term in liver tissue, and have a well-tolerated safety profile. Our findings support the further development of telmisartan prodrugs that enable infrequent dosing in the treatment of liver fibrosis.
Date issued
2018-11-20Department
Massachusetts Institute of Technology. Department of ChemistryJournal
Nature Biomedical Engineering
Publisher
Springer Nature
Citation
Golder, Matthew R. et al. "Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs." Nature Biomedical Engineering 2, 11 (November 2018): 822-830 © 2018 The Author(s)
Version: Author's final manuscript
ISSN
2157-846X