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

McGuigan, Christopher, Serpi, Michaela, Bibbo, Rita, Roberts, Helen Christina, Hughes, Clare Elizabeth, Caterson, Bruce, Gibert, Ana Torrent and Verson, Carlos Raul Alaez 2008. 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 51 (18) , pp. 5807-5812. 10.1021/jm800594c

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QD Chemistry
Q Science > QP Physiology
R Medicine > RB Pathology
R Medicine > RM Therapeutics. Pharmacology
Publisher: ACS Publications
ISSN: 0022-2623
Last Modified: 03 Nov 2017 01:11
URI: http://orca.cf.ac.uk/id/eprint/9166

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Cited 13 times in Scopus. View in Scopus. Powered By Scopus® Data

Cited 8 times in Web of Science. View in Web of Science.

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