title: Phosphate prodrugs derived from N-acetylglucosamine have enhanced chondroprotective activity in explant cultures and represent a new lead in antiosteoarthritis drug discovery.
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.
authors: Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK. mcguigan@cardiff.ac.uk
authors: Christopher
authors: C
authors: McGuigan
authors: Michaela
authors: M
authors: Serpi
authors: Rita
authors: R
authors: Bibbo
authors: Helen
authors: H
authors: Roberts
authors: Clare
authors: C
authors: Hughes
authors: Bruce
authors: B
authors: Caterson
authors: Ana Torrent
authors: AT
authors: Gibert
authors: Carlos Raúl Alaez
authors: CR
authors: Verson
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry*; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects*; D002417:Cattle; D015195:Drug Design; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D010003:Osteoarthritis / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D011355:Prodrugs; D000117:Acetylglucosamine