Phosphate prodrugs derived from N-acetylglucosamine have enhanced chondroprotective activity in explant cultures and represent a new lead in antiosteoarthritis drug discovery

Journal of Medicinal Chemistry
Christopher McGuiganCarlos Raúl Alaez Verson

Abstract

We report the application of the phosphoramidate ProTide approach, developed by us for antiviral nucleosides, to sugar derivatives with potential chondroprotection against osteoarthritis. In particular, N-acetylglucosamine was converted to a series of 06 arylaminoacyl phosphoramidates with ester and amino acid variation. Compounds were prepared by two routes, with or without sugar protection, and were isolated as phosphate diastereoisomers. The compounds were assayed for cellular toxicity and for inhibition of IL-1 induced glycosaminoglycan (GAG) release (i.e., proteoglycan degradation) from bovine articular cartilage in vitro explant cultures. By comparison to the N-acetyl glucosamine parent, some of the analogues show a significant enhancement in efficacy in the inhibition of inflammatory cytokine-induced proteoglycan degradation.

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Citations

Mar 31, 2012·Future Medicinal Chemistry·Karolina Madela, Christopher McGuigan
Sep 30, 2010·Biochemical and Biophysical Research Communications·Masatoshi HayashiNaoki Ishiguro
Jun 1, 2011·Biochemical and Biophysical Research Communications·Masatoshi HayashiNaoki Ishiguro
Dec 25, 2016·Chembiochem : a European Journal of Chemical Biology·Anna SchüllerGünter Mayer
Jun 19, 2013·Current Protocols in Nucleic Acid Chemistry·Michaela SerpiMagdalena Slusarczyk
May 25, 2018·Antiviral Chemistry & Chemotherapy·Magdalena SlusarczykFabrizio Pertusati
May 15, 2021·Expert Opinion on Drug Discovery·Michaela Serpi, Fabrizio Pertusati
Aug 10, 2017·Journal of Medicinal Chemistry·Youcef MehellouJan Balzarini
Aug 7, 2019·Journal of Medicinal Chemistry·Chiara MorozziFabrizio Pertusati
Nov 24, 2021·Organic & Biomolecular Chemistry·Yuan-Yuan ZhuShang-Dong Yang

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