Adenosine kinase inhibitors. 3. Synthesis, SAR, and antiinflammatory activity of a series of l-lyxofuranosyl nucleosides.
J Med Chem
; 46(22): 4750-60, 2003 Oct 23.
Article
em En
| MEDLINE
| ID: mdl-14561094
ABSTRACT
Chronic inflammatory diseases, such as arthritis and rheumatoid arthritis, remain major health problems worldwide. We previously demonstrated that adenosine kinase inhibitors (AKIs) exhibit antiinflammatory effects by inhibiting TNF-alpha production, neutrophil accumulation, and edema formation. Although adenosine receptor agonists produce similar effects, AKIs showed the antiinflammatory activity without the cardiovascular side effects that prevented the development of adenosine receptor specific agonists. However, previously described potent AKIs, such as 5-iodotubercidin, are nucleosides which have the potential to undergo in vivo 5'-O-phosphorylation and therefore produce cytotoxicity. In an effort to eliminate toxicities produced by phosphorylated nucleosides, l-lyxofuranosyl analogues of tubercidin were tested as potential AKIs since the opposite stereochemical orientation of the CH(2)OH was expected to eliminate intracellular phosphorylation. Described herein are the discovery of a new series of AKIs based on alpha-l-lyxofuranosyl nucleosides, their SAR, as well as the antiinflammatory activity of the lead compound GP790 (IC(50) = 0.47 nM, 47% inhibition of paw swelling at 10 mg/kg in rat carrageenan paw edema model). In addition, a study showing that in the skin lesion model the antiinflammatory activity is reversed by an A2 selective adenosine receptor antagonist 3,7-dimethyl-1-propargyl xanthine [correction of propylxanthine] (DMPX) is also described.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Teobromina
/
Adenosina Quinase
/
Anti-Inflamatórios não Esteroides
/
Nucleosídeos
Limite:
Animals
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Estados Unidos