title: Novel phosphoramidate prodrugs of N-acetyl-(D)-glucosamine with antidegenerative activity on bovine and human cartilage explants.
abstract: (D)-Glucosamine and other nutritional supplements have emerged as safe alternative therapies for osteoarthritis (OA), a chronic and degenerative articular joint disease. In our preceding paper, a series of novel O-6 phosphate N-acetyl (d)-glucosamine prodrugs aimed at improving the oral bioavailability of N-acetyl-(d)-glucosamine as its putative bioactive phosphate form were shown to have greater chondroprotective activity in vitro when compared to the parent agent. In order to extend the SAR studies, this work focuses on the O-3 and O-4 phosphate prodrugs of N-acetyl-(d)-glucosamine bearing a 4-methoxy phenyl group and different amino acid esters on the phosphate moiety. Among the compounds, the (l)-proline amino acid-containing prodrugs proved to be the most active of the series, more effective than the prior O-6 compounds, and well processed in chondrocytes in vitro. Data on human cartilage support the notion that these novel O-3 and O-4 regioisomers may represent novel promising leads for drug discovery for osteoarthritis.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Serpi
authors.forename: Rita
authors.initials: R
authors.lastname: Bibbo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rat
authors.forename: Helen
authors.initials: H
authors.lastname: Roberts
authors.forename: Claire
authors.initials: C
authors.lastname: Hughes
authors.forename: Bruce
authors.initials: B
authors.lastname: Caterson
authors.forename: María José
authors.initials: MJ
authors.lastname: Alcaraz
authors.forename: Anna Torrent
authors.initials: AT
authors.lastname: Gibert
authors.forename: Carlos Raul Alaez
authors.initials: CR
authors.lastname: Verson
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D004355:Drug Stability; D006025:Glycosaminoglycans / Q000378:metabolism; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D009924:Organ Culture Techniques; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010003:Osteoarthritis / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D053674:Aggrecans; D006025:Glycosaminoglycans; D009943:Organophosphorus Compounds; D011355:Prodrugs; C020341:glucosaminoglycans; D000117:Acetylglucosamine