Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs.

Autor: Golder MR; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA., Liu J; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.; XTuit Pharmaceuticals, Waltham, MA, USA., Andersen JN; XTuit Pharmaceuticals, Waltham, MA, USA., Shipitsin MV; XTuit Pharmaceuticals, Waltham, MA, USA., Vohidov F; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA., Nguyen HV; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA., Ehrlich DC; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA., Huh SJ; XTuit Pharmaceuticals, Waltham, MA, USA., Vangamudi B; XTuit Pharmaceuticals, Waltham, MA, USA., Economides KD; XTuit Pharmaceuticals, Waltham, MA, USA., Neenan AM; XTuit Pharmaceuticals, Waltham, MA, USA., Ackley JC; XTuit Pharmaceuticals, Waltham, MA, USA., Baddour J; XTuit Pharmaceuticals, Waltham, MA, USA., Paramasivan S; XTuit Pharmaceuticals, Waltham, MA, USA., Brady SW; XTuit Pharmaceuticals, Waltham, MA, USA., Held EJ; XTuit Pharmaceuticals, Waltham, MA, USA., Reiter LA; XTuit Pharmaceuticals, Waltham, MA, USA., Saucier-Sawyer JK; XTuit Pharmaceuticals, Waltham, MA, USA., Kopesky PW; XTuit Pharmaceuticals, Waltham, MA, USA., Chickering DE; XTuit Pharmaceuticals, Waltham, MA, USA., Blume-Jensen P; XTuit Pharmaceuticals, Waltham, MA, USA. pblumejensen@xtuit.com.; Acrivon Therapeutics, Lab Central, Cambridge, MA, USA. pblumejensen@xtuit.com., Johnson JA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. jaj2109@mit.edu.
Jazyk: angličtina
Zdroj: Nature biomedical engineering [Nat Biomed Eng] 2018 Nov; Vol. 2 (11), pp. 822-830. Date of Electronic Publication: 2018 Aug 20.
DOI: 10.1038/s41551-018-0279-x
Abstrakt: 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 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.
Competing Interests: Competing interests J.L., J.N.A, M.V.S, S.J.H, B.V., K.D.E, A.M.N., J.C.A., J.B., S.P., S.W.B., E.J.H., J.K.S-S., P.W.K., D.E.C., and P.B.-J. are former employees and shareholders of XTuit Pharmaceuticals. P.B.-J. is President and Founder of Acrivon Therapeutics. J.A.J. is a Co-Founder of Acrivon Therapeutics.
Databáze: MEDLINE
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