Novel Phosphoramidate Prodrugs of N-Acetyl-(d)-Glucosamine with Antidegenerative Activity on Bovine and Human Cartilage Explants

• Published in: Journal of medicinal chemistry Vol. 55; no. 10; pp. 4629 - 4639
• Main Authors: Serpi, Michaela, Bibbo, Rita, Rat, Stephanie, Roberts, Helen, Hughes, Claire, Caterson, Bruce, Alcaraz, María José, Gibert, Anna Torrent, Verson, Carlos Raul Alaez, McGuigan, Christopher
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.05.2012; Amer Chemical Soc
• Subjects: Acetylglucosamine - analogs & derivatives; Acetylglucosamine - chemical synthesis; Acetylglucosamine - pharmacology; Aggrecans - metabolism; Animals; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cattle; Chemistry, Medicinal; Chondrocytes - drug effects; Chondrocytes - metabolism; Drug Stability; Glycosaminoglycans - metabolism; Guinea Pigs; Half-Life; Humans; Life Sciences & Biomedicine; Organ Culture Techniques; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - pharmacology; Osteoarthritis - drug therapy; Pharmacology & Pharmacy; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; N-ACETYLGLUCOSAMINE; CHONDROITIN SULFATE; PLACEBO; SINGLE; PHARMACOKINETICS; OSTEOARTHRITIS; GLYCOSYLATION; GLUCOSAMINE HYDROCHLORIDE; DERIVATIVES; BIOAVAILABILITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300074y

(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.