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Novel phosphoramidate prodrugs of N-Acetyl-(d)-Glucosamine with antidegenerative activity on bovine and human cartilage explants

Serpi, Michaela, Bibbo, Rita, Rat, Stephanie, Roberts, Helen Christina, Hughes, Clare Elizabeth, Caterson, Bruce, Alcaraz, María José, Gibert, Anna Torrent, Verson, Carlos Raul Alaez and McGuigan, Christopher 2012. Novel phosphoramidate prodrugs of N-Acetyl-(d)-Glucosamine with antidegenerative activity on bovine and human cartilage explants. Journal of Medicinal Chemistry 55 (10) , pp. 4629-4639. 10.1021/jm300074y

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RM Therapeutics. Pharmacology
Publisher: ACS Publications
ISSN: 0022-2623
Last Modified: 09 Apr 2019 20:32
URI: http://orca.cf.ac.uk/id/eprint/32135

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